138 results on '"Goffin, Vincent"'
Search Results
2. Immunomodulatory role of decidual prolactin on the human fetal membranes and placenta.
- Author
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Flores-Espinosa P, Méndez I, Irles C, Olmos-Ortiz A, Helguera-Repetto C, Mancilla-Herrera I, Ortuño-Sahagún D, Goffin V, and Zaga-Clavellina V
- Subjects
- Pregnancy, Female, Humans, Placenta, Extraembryonic Membranes, Amniotic Fluid, Prolactin, Decidua
- Abstract
The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Flores-Espinosa, Méndez, Irles, Olmos-Ortiz, Helguera-Repetto, Mancilla-Herrera, Ortuño-Sahagún, Goffin and Zaga-Clavellina.)
- Published
- 2023
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3. Prolactin Regulates Testicular Gene Expression and Cell Cycle Processes Predominantly via JAK2/STAT5 Pathway in the Male Rat.
- Author
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Raut S, Khambata K, Goffin V, and Balasinor N
- Subjects
- Rats, Animals, Male, STAT5 Transcription Factor genetics, STAT5 Transcription Factor metabolism, Phosphatidylinositol 3-Kinases metabolism, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Cell Division, Gene Expression, Nuclear Proteins metabolism, Prolactin metabolism, Testis metabolism
- Abstract
Hyperprolactinemia is prevalent in up to 16% of infertile males. Although the prolactin receptor (PRLR) is present on various testicular cells, the physiological role of this receptor in spermatogenesis remains elusive. The aim of this study is to delineate prolactin actions in rat testicular tissue. Serum prolactin, developmental expression of PRLR, signaling pathways associated, and gene transcription regulation in the testes were investigated. Serum prolactin and testicular PRLR expression was found to be significantly increased at pubertal and adult ages as compared to prepubertal. Further, PRLR activated the JAK2/STAT5 pathway, but not the MAPK/ERK and PI3K/AKT pathway in the testicular cells. Gene expression profiling following prolactin treatment in seminiferous tubule culture resulted in a total of 692 differentially expressed genes, of which 405 were upregulated and 287 were downregulated. Enrichment map analysis showed that prolactin target genes are involved in processes such as cell cycle, male reproduction, chromatin remodeling, and cytoskeletal organization. Novel gene targets of prolactin whose role in testes is unexplored were obtained and validated by qPCR. Additionally, 10 genes involved in cell cycle process were also validated; 6 genes (Ccna1, Ccnb1, Ccnb2, Cdc25a, Cdc27, Plk1) were found to be significantly upregulated, whereas 4 genes (Ccar2, Nudc, Tuba1c, Tubb2a) were found to be significantly downregulated in testes after treatment with prolactin. Taken together, the findings from this study suggest a crucial role of prolactin in male reproduction and identified target genes regulated by prolactin in the testes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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4. Sex-dependent pain trajectories induced by prolactin require an inflammatory response for pain resolution.
- Author
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Mecklenburg J, Wangzhou A, Hovhannisyan AH, Barba-Escobedo P, Shein SA, Zou Y, Weldon K, Lai Z, Goffin V, Dussor G, Tumanov AV, Price TJ, and Akopian AN
- Subjects
- Animals, Female, Ganglia, Spinal, Male, Mice, Pain, Sensory Receptor Cells, Prolactin pharmacology, Receptors, Prolactin genetics
- Abstract
Pain development and resolution patterns in many diseases are sex-dependent. This study aimed to develop pain models with sex-dependent resolution trajectories, and identify factors linked to resolution of pain in females and males. Using different intra-plantar (i.pl.) treatment protocols with prolactin (PRL), we established models with distinct, sex-dependent patterns for development and resolution of pain. An acute PRL-evoked pain trajectory, in which hypersensitivity is fully resolved within 1 day, showed substantial transcriptional changes after pain-resolution in female and male hindpaws and in the dorsal root ganglia (DRG). This finding supports the notion that pain resolution is an active process. Prolonged treatment with PRL high dose (1 μg) evoked mechanical hypersensitivity that resolved within 5-7 days in mice of both sexes and exhibited a pro-inflammatory transcriptional response in the hindpaw, but not DRG, at the time point preceding resolution. Flow cytometry analysis linked pro-inflammatory responses in female hindpaws to macrophages/monocytes, especially CD11b
+ /CD64+ /MHCII+ cell accumulation. Prolonged low dose PRL (0.1 μg) treatment caused non-resolving mechanical hypersensitivity only in females. This effect was independent of sensory neuronal PRLR and was associated with a lack of immune response in the hindpaw, although many genes underlying tissue damage were affected. We conclude that different i.pl. PRL treatment protocols generates distinct, sex-specific pain hypersensitivity resolution patterns. PRL-induced pain resolution is preceded by a pro-inflammatory macrophage/monocyte-associated response in the hindpaws of mice of both sexes. On the other hand, the absence of a peripheral inflammatory response creates a permissive condition for PRL-induced pain persistency in females., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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5. Meningeal CGRP-Prolactin Interaction Evokes Female-Specific Migraine Behavior.
- Author
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Avona A, Mason BN, Burgos-Vega C, Hovhannisyan AH, Belugin SN, Mecklenburg J, Goffin V, Wajahat N, Price TJ, Akopian AN, and Dussor G
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Rats, Rats, Sprague-Dawley, Sex Characteristics, Calcitonin Gene-Related Peptide metabolism, Meninges metabolism, Migraine Disorders metabolism, Prolactin metabolism
- Abstract
Objective: Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female-specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges., Methods: Prolactin, CGRP, and receptor antagonists CGRP8-37 or Δ1-9-G129R-hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back-labeled trigeminal ganglia (TG) neurons was used to assess PRL-induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured., Results: We found that dural PRL produced sustained and long-lasting migraine-like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little-to-no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8-37 decreases migraine-like responses to dural PRL. Reciprocally, Δ1-9-G129R-hPRL attenuates dural CGRP-induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine-like responses to dural CGRP., Interpretation: This CGRP-PRL interaction in the meninges is a mechanism by which these peptides could produce female-selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129-1144., (© 2021 American Neurological Association.)
- Published
- 2021
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6. Prolactin and its receptor as therapeutic targets in glioblastoma multiforme.
- Author
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Asad AS, Nicola Candia AJ, Gonzalez N, Zuccato CF, Abt A, Orrillo SJ, Lastra Y, De Simone E, Boutillon F, Goffin V, Seilicovich A, Pisera DA, Ferraris MJ, and Candolfi M
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Movement genetics, Cell Movement physiology, Cell Proliferation genetics, Cell Proliferation physiology, Female, Glioblastoma drug therapy, Glioblastoma genetics, Glioma genetics, Humans, Male, Plasmids genetics, Prolactin genetics, Protein Binding genetics, Rats, Receptors, Prolactin genetics, Signal Transduction drug effects, Signal Transduction genetics, Treatment Outcome, Glioblastoma metabolism, Glioma metabolism, Prolactin metabolism, Receptors, Prolactin metabolism
- Abstract
Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1-9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL
+ /PRLRHIGH GBM performed worse than PRL+ /PRLRLOW GBM. In contrast, all male PRL+ /PRLRHIGH GII-III patients were alive whereas only 30% of PRL+ /PRLRLOW GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.- Published
- 2019
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7. Prolactin Promotes Fibrosis and Pancreatic Cancer Progression.
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Tandon M, Coudriet GM, Criscimanna A, Socorro M, Eliliwi M, Singhi AD, Cruz-Monserrate Z, Bailey P, Lotze MT, Zeh H, Hu J, Goffin V, Gittes GK, Biankin AV, and Esni F
- Subjects
- Animals, Carcinoma, Pancreatic Ductal physiopathology, Cell Line, Tumor, Collagen metabolism, Disease Progression, Epithelium metabolism, Female, Fibrosis, Focal Adhesion Kinase 1 metabolism, Genes, Reporter, HMGB1 Protein physiology, Humans, Macrophages metabolism, Male, Metoclopramide, Mice, Mice, Knockout, Neoplasm Proteins metabolism, Neoplasms, Hormone-Dependent physiopathology, Pancreatic Neoplasms physiopathology, Phosphorylation, Pregnancy, Prolactin deficiency, Prolactin physiology, Protein Processing, Post-Translational, RNA Interference, RNA, Small Interfering genetics, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Recombinant Proteins pharmacology, STAT3 Transcription Factor metabolism, Stromal Cells metabolism, Carcinoma, Pancreatic Ductal pathology, Neoplasms, Hormone-Dependent pathology, Pancreatic Neoplasms pathology, Prolactin pharmacology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1-induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer. SIGNIFICANCE: Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression., (©2019 American Association for Cancer Research.)
- Published
- 2019
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8. Paul Kelly, PhD (1943-2018).
- Author
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Goffin V, Zingg HH, Sumida C, Touraine P, and Friesen HG
- Subjects
- Canada, History, 20th Century, History, 21st Century, Humans, Prolactin, Research Personnel
- Published
- 2019
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9. JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes.
- Author
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de Dios N, Orrillo S, Irizarri M, Theas MS, Boutillon F, Candolfi M, Seilicovich A, Goffin V, Pisera D, and Ferraris J
- Subjects
- Animals, Cell Proliferation drug effects, Cell Proliferation physiology, Female, Lactotrophs drug effects, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt metabolism, Rats, Rats, Wistar, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism, Signal Transduction drug effects, Apoptosis drug effects, Janus Kinase 2 metabolism, Lactotrophs metabolism, Prolactin pharmacology, STAT5 Transcription Factor metabolism, Signal Transduction physiology
- Abstract
Prolactinomas are increasingly viewed as a "problem of signal transduction." Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas., (© 2018 S. Karger AG, Basel.)
- Published
- 2019
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10. ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage.
- Author
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Karayazi Atici Ö, Urbanska A, Gopinathan SG, Boutillon F, Goffin V, and Shemanko CS
- Subjects
- Cell Survival drug effects, Cells, Cultured, Clone Cells drug effects, Clone Cells physiology, DNA Damage genetics, Female, Humans, MCF-7 Cells, Ataxia Telangiectasia Mutated Proteins physiology, Cell Proliferation drug effects, DNA Damage drug effects, HSP90 Heat-Shock Proteins metabolism, Prolactin pharmacology
- Abstract
Prolactin (PRL) acts as a survival factor for breast cancer cells, but the PRL signaling pathway and the mechanism are unknown. Previously, we identified the master chaperone, heat shock protein 90 (HSP90) α, as a prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) target gene involved in survival, and here we investigated the role of HSP90 in the mechanism of PRL-induced viability in response to DNA damage. The ataxia-telangiectasia mutated kinase (ATM) protein plays a critical role in the cellular response to double-strand DNA damage. We observed that PRL increased viability of breast cancer cells treated with doxorubicin or etoposide. The increase in cellular resistance is specific to the PRL receptor, because the PRL receptor antagonist, Δ1-9-G129R-hPRL, prevented the increase in viability. Two different HSP90 inhibitors, 17-allylamino-17-demethoxygeldanamycin and BIIB021, reduced the PRL-mediated increase in cell viability of doxorubicin-treated cells and led to a decrease in JAK2, ATM, and phosphorylated ATM protein levels. Inhibitors of JAK2 (G6) and ATM (KU55933) abolished the PRL-mediated increase in cell viability of DNA-damaged cells, supporting the involvement of each, as well as the crosstalk of ATM with the PRL pathway in the context of DNA damage. Drug synergism was detected between the ATM inhibitor (KU55933) and doxorubicin and between the HSP90 inhibitor (BIIB021) and doxorubicin. Short interfering RNA directed against ATM prevented the PRL-mediated increase in cell survival in two-dimensional cell culture, three-dimensional collagen gel cultures, and clonogenic cell survival, after doxorubicin treatment. Our results indicate that ATM contributes to the PRL-JAK2-STAT5-HSP90 pathway in mediating cellular resistance to DNA-damaging agents., (Copyright © 2018 Endocrine Society.)
- Published
- 2018
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11. Novel reagents for human prolactin research: large-scale preparation and characterization of prolactin receptor extracellular domain, non-pegylated and pegylated prolactin and prolactin receptor antagonist.
- Author
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Oclon E, Solomon G, Hayouka Z, Salame TM, Goffin V, and Gertler A
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- Humans, Chromatography, Gel, Multiprotein Complexes chemistry, Prolactin chemistry, Receptors, Prolactin chemistry, Surface Plasmon Resonance
- Abstract
To provide new tools for in vitro and in vivo prolactin (PRL) research, novel protocols for large-scale preparation of untagged human PRL (hPRL), a hPRL antagonist (del 1-9-G129R hPRL) that acts as a pure antagonist of hPRL in binding to hPRL receptor extracellular domain (hPRLR-ECD), and hPRLR-ECD are demonstrated. The interaction of del 1-9-G129R hPRL with hPRLR-ECD was demonstrated by competitive non-radioactive binding assay using biotinylated hPRL as the ligand and hPRLR-ECD as the receptor, by formation of stable 1:1 complexes with hPRLR-ECD under non-denaturing conditions using size-exclusion chromatography, and by surface plasmon resonance methodology. In all three types of experiments, the interaction of del 1-9-G129R hPRL was equal to that of unmodified hPRL. Del 1-9-G129R hPRL inhibited the hPRL-induced proliferation of Baf/LP cells stably expressing hPRLR. Overall, the biological properties of del 1-9-G129R hPRL prepared by the protocol described herein were similar to those of the antagonist prepared using the protocol reported in the original study; however, the newly described protocol improved yields by >6-fold. To provide long-lasting hPRL as a new reagent needed for in vivo experiments, we prepared its mono-pegylated analogue and found that pegylation lowers its biological activity in a homologous in vitro assay. As its future use will require the development of a PRL antagonist with highly elevated affinity, del 1-9-G129R hPRL was expressed on the surface of yeast cells. It retained its binding capacity for hPRLR-ECD, and this methodology was shown to be suitable for future development of high-affinity hPRL antagonists using a library of randomly mutated open reading frame of del 1-9-G129R hPRL and selecting high-affinity mutants by yeast surface display methodology., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2018
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12. Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge.
- Author
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Goffin V
- Subjects
- Animals, Breast Neoplasms drug therapy, Female, Humans, Male, Prostatic Neoplasms drug therapy, Receptors, Prolactin antagonists & inhibitors, Signal Transduction, Breast Neoplasms metabolism, Prolactin metabolism, Prostatic Neoplasms metabolism, Receptors, Prolactin metabolism
- Abstract
In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors. Nevertheless, the PRLR neutralizing antibody LFA102 tested recently in a Phase I trial in advanced, PRLR-positive prostate cancer and breast cancer patients failed to provide any clinical benefit. This underlines the need to better understand the actual impact of PRLR signaling on the progression of these cancers. Canonical PRLR-triggered signaling cascades include STAT5A/B, ERK1/2, PI3K/Akt, FAK and Src family kinases. Recent studies suggested that the nature and the outcome of PRLR signaling might be markedly different in breast than in prostate cancer. In the latter, like in many organs, PRLR/STAT5 signaling acts as a pro-tumorigenic pathway. In particular, it promotes the amplification of treatment-resistant prostate stem/progenitor cells, predicts early cancer recurrence and favors metastatic dissemination. In contrast, PRLR/STAT5 signaling was recently proposed to prevent breast cancer cell dissemination and to predict favorable clinical outcomes. While there is no evidence that pathways other than STAT5 are activated by prolactin in the prostate, these alternate signaling cascades may be primarily responsible for the pro-tumorigenic effects of prolactin in breast cancer. If these conclusions are confirmed in future studies, the therapeutic targeting of PRLR signaling in breast and prostate cancer may warrant the development of organ-specific strategies., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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13. Alpha 2 -adrenoceptor agonists trigger prolactin signaling in breast cancer cells.
- Author
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Castillo LF, Rivero EM, Goffin V, and Lüthy IA
- Subjects
- Animals, Autocrine Communication drug effects, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cattle, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Humans, MCF-7 Cells, Microscopy, Fluorescence, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt metabolism, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, STAT5 Transcription Factor metabolism, Adrenergic alpha-2 Receptor Agonists pharmacology, Dexmedetomidine pharmacology, Prolactin pharmacology, Signal Transduction drug effects
- Abstract
Breast cancer is the most frequent malignancy among women worldwide. We have described the expression of α
2 -adrenoceptors in breast cancer cell lines, associated with increased cell proliferation and tumor growth. A mitogenic autocrine/paracrine loop of prolactin (Prl) has been described in breast cancer cells. We hypothesized that the α2 -adrenergic enhancement of proliferation could be mediated, at least in part, by this Prl loop. In both T47D and MCF-7 cell lines, the incubation with the α2 -adrenergic agonist dexmedetomidine significantly increased Prl release into the culture medium (measured by the Nb2 bioassay), this effect being reversed by the α2 -adrenergic antagonist rauwolscine. No change in Prl receptors (PrlR) was observed by RT-qPCR in these cell lines. In IBH-6 cells a decrease in Prl secretion was observed at the lower dexmedetomidine concentration. The signaling pathways involved in ovine Prl (oPrl) and dexmedetomidine action were also assessed. Both compounds significantly activated STAT5 and ERK in all three cell lines. In T47D and MCF-7 cell lines also AKT was activated by both Prl and dexmedetomidine. We therefore describe the STAT5 phosphorylation by an α2 -adrenergic agonist, dexmedetomidine. In T47D cells, the α2 -adrenergic stimulation of cell proliferation is probably mediated, at least in part, by the Prl autocrine/paracrine loop, because this effect is abrogated by the specific PrlR antagonist Δ1-9-G129R-hPrl. The implication of Prl loop describes a novel mechanism of action of this GPCR., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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14. Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death.
- Author
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Meléndez García R, Arredondo Zamarripa D, Arnold E, Ruiz-Herrera X, Noguez Imm R, Baeza Cruz G, Adán N, Binart N, Riesgo-Escovar J, Goffin V, Ordaz B, Peña-Ortega F, Martínez-Torres A, Clapp C, and Thebault S
- Subjects
- Animals, Apoptosis drug effects, Female, Glutathione metabolism, Humans, Male, Mice, Prolactin genetics, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Retinal Pigment Epithelium metabolism, Sirtuin 2 genetics, TRPM Cation Channels genetics, Aging physiology, Prolactin metabolism, Retinal Pigment Epithelium cytology, Sirtuin 2 metabolism, TRPM Cation Channels metabolism
- Abstract
The identification of pathways necessary for retinal pigment epithelium (RPE) function is fundamental to uncover therapies for blindness. Prolactin (PRL) receptors are expressed in the retina, but nothing is known about the role of PRL in RPE. Using the adult RPE 19 (ARPE-19) human cell line and mouse RPE, we identified the presence of PRL receptors and demonstrated that PRL is necessary for RPE cell survival via anti-apoptotic and antioxidant actions. PRL promotes the antioxidant capacity of ARPE-19 cells by reducing glutathione. It also blocks the hydrogen peroxide-induced increase in deacetylase sirtuin 2 (SIRT2) expression, which inhibits the TRPM2-mediated intracellular Ca(2+) rise associated with reduced survival under oxidant conditions. RPE from PRL receptor-null (prlr(-/-)) mice showed increased levels of oxidative stress, Sirt2 expression and apoptosis, effects that were exacerbated in animals with advancing age. These observations identify PRL as a regulator of RPE homeostasis., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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15. The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation.
- Author
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Sutherland A, Forsyth A, Cong Y, Grant L, Juan TH, Lee JK, Klimowicz A, Petrillo SK, Hu J, Chan A, Boutillon F, Goffin V, Egan C, Tang PA, Cai L, Morris D, Magliocco A, and Shemanko CS
- Subjects
- Adult, Aged, Bone Neoplasms chemistry, Bone Neoplasms secondary, Breast Neoplasms chemistry, Breast Neoplasms pathology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Middle Aged, Neoplastic Cells, Circulating chemistry, Odds Ratio, Prolactin analysis, Proportional Hazards Models, Receptors, Prolactin analysis, Time Factors, Tissue Array Analysis, Bone Neoplasms metabolism, Breast Neoplasms metabolism, Cell Differentiation, Hedgehog Proteins metabolism, Osteoclasts metabolism, Osteoclasts pathology, Prolactin metabolism, Receptors, Prolactin metabolism, Signal Transduction
- Abstract
Background: Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment., Methods: We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases. A Cox proportional hazards regression model was fitted to evaluate the associations between high prolactin receptor (PRLR) expression and time to bone metastasis, adjusting for estrogen receptor status, lymph node status, and chemotherapy status. We assessed osteoclast differentiation, osteoclast size, and measured pit formation in dentine slices. Statistical tests were two-sided., Results: High PRLR expression in the primary breast tumor was associated with a shorter time to metastasis that includes bone (PRLRAQUA Max-per 100 unit hazard ratio = 1.04, 95% confidence interval = 1.00 to 1.07, P = .03). We observed the PRLR in rare samples of bone metastases and matched primary breast cancer. PRL treatment of breast cancer cells induced osteoclast differentiation and bone lysis via secreted factors and was abrogated by a PRLR antagonist (delta1-9-G129R-hPRL). We demonstrated that sonic hedgehog is a PRL-regulated cytokine in breast cancer cells and part of the mechanism that induces osteoclast differentiation., Conclusions: Our evidence indicates that PRL-PRLR can escalate the impact of breast cancer on bone metastasis and that the presence of the PRLR in the tumor microenvironment of breast cancer bone metastasis has the potential to modulate the microenvironment to induce lytic osteoclast formation., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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16. Human and murine prostate basal/stem cells are not direct targets of prolactin.
- Author
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Sackmann-Sala L, Angelergues A, Boutillon F, d'Acremont B, Maidenberg M, Oudard S, and Goffin V
- Subjects
- Animals, Humans, Male, Mice, Receptors, Prolactin, Signal Transduction, Prolactin metabolism, Prostatic Neoplasms metabolism, Stem Cells metabolism
- Abstract
Local overexpression of prolactin (PRL) in the prostate of Pb-PRL transgenic mice induces benign prostate tumors exhibiting marked amplification of the epithelial basal/stem cell compartment. However, PRL-activated intracellular signaling seems to be restricted to luminal cells, suggesting that basal/stem cells may not be direct targets of PRL. Given their described role as prostate cancer-initiating cells, it is important to understand the mechanisms that regulate basal/stem cells. In this study, we evaluated whether PRL can act directly on these cells, by growing them as prostaspheres. For this, primary 3D prostasphere cultures were prepared from unfractionated cells isolated from freshly harvested human and mouse benign prostate tissues and subjected to PRL stimulation in vitro. None of the various concentrations of PRL tested showed any effects on the sizes or numbers of the prostaspheres generated. In addition, neither activation of canonical PRL-induced signaling pathways (Stat5, Stat3 or Erk1/2) nor increased expression of the proliferation marker Ki-67 were detected by immunostaining in PRL-stimulated prostaspheres. Consistent with the absence of response, PRL receptor mRNA levels were generally undetectable in mouse sphere cells. We conclude that human and mouse prostate basal/stem cells are not direct targets of PRL action. The observed amplification of basal/stem cells in Pb-PRL prostates might be due to paracrine mechanisms originating from PRL action on other cell compartments. Our current efforts are aimed at unraveling these mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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17. Hypothalamic Prolactin Regulation of Luteinizing Hormone Secretion in the Female Rat.
- Author
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Grachev P, Li XF, Goffin V, and O'Byrne KT
- Subjects
- Animals, Estradiol pharmacology, Female, Hyperprolactinemia metabolism, Hypothalamus metabolism, Luteinizing Hormone blood, Ovariectomy, Prolactin metabolism, Rats, Rats, Sprague-Dawley, Receptors, Prolactin metabolism, Sex Factors, Signal Transduction drug effects, Signal Transduction physiology, Hypothalamus drug effects, Luteinizing Hormone metabolism, Prolactin pharmacology
- Abstract
Prolactin (PRL) levels increase in response to long-term antipsychotic treatment that disrupts reproductive function. Recent evidence suggests that activation of central PRL receptors (PRLR) inhibits LH secretion and in ovariectomized rats. However, the mechanisms involved, the mode of LH secretion affected and relevance to hyperprolactinemia remain unknown. We therefore investigated the contribution of central PRL/PRLR signaling to the control of estradiol-induced surges of LH and PRL and pulsatile LH secretion under basal and hyperprolactinemic conditions. First, by subjecting ovariectomized estradiol-primed rats intracerebroventricularly administered with PRL to frequent blood sampling, we demonstrated that acute activation of hypothalamic PRLR disrupts pulsatile LH secretion. Pretreatment (intracerebroventricularly) with the pure PRLR antagonist, Δ1-9-G129R-hPRL, or the γ-aminobutyric acid receptor type A antagonist, bicuculline, blocked this effect. Next, we revealed that sustained blockade of hypothalamic PRLR using Δ1-9-G129R-hPRL augmented the magnitude of LH surges induced by estradiol benzoate and progesterone treatment and suppressed the concomitant surges of PRL. Finally, we determined that acute antagonism of central PRLR is insufficient to normalize the duration of the LH pulse interval prolonged as a result of hyperprolactinemia induced by chronic exposure to the atypical antipsychotic sulpiride. These data serve as the first evidence to suggest that PRL signaling through hypothalamic PRLR inhibits pulsatile secretion of LH in a γ-aminobutyric acid receptor type A-dependent fashion and tonically restrains the magnitude of the LH surge. Furthermore, our results indicate that transient blockade of hypothalamic PRL/PRLR signaling is not an effective strategy for restoring LH pulsatility perturbed by chronic hyperprolactinemia.
- Published
- 2015
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18. Minireview: prolactin regulation of adult stem cells.
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Sackmann-Sala L, Guidotti JE, and Goffin V
- Subjects
- Animals, Cell Differentiation, Cell Self Renewal, Humans, Signal Transduction, Adult Stem Cells physiology, Prolactin physiology
- Abstract
Adult stem/progenitor cells are found in many tissues, where their primary role is to maintain homeostasis. Recent studies have evaluated the regulation of adult stem/progenitor cells by prolactin in various target tissues or cell types, including the mammary gland, the prostate, the brain, the bone marrow, the hair follicle, and colon cancer cells. Depending on the tissue, prolactin can either maintain stem cell quiescence or, in contrast, promote stem/progenitor cell expansion and push their progeny towards differentiation. In many instances, whether these effects are direct or involve paracrine regulators remains debated. This minireview aims to overview the current knowledge in the field.
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- 2015
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19. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications.
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Goffin V and Touraine P
- Subjects
- Animals, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Drug Design, Female, Humans, Male, Molecular Targeted Therapy, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Receptors, Prolactin metabolism, Antineoplastic Agents pharmacology, Prolactin metabolism, Receptors, Prolactin antagonists & inhibitors
- Abstract
Introduction: Prolactin (PRL) signaling has emerged as a relevant target in breast and prostate cancers. This has encouraged various laboratories to develop compounds targeting the PRL receptor (PRLR). As the latter is widely distributed, it is timely to address whether other conditions could also benefit from such inhibitors., Areas Covered: The authors briefly overview the two classes of PRLR blockers, which involve: i) PRL-core based analogs that have been validated as competitive antagonists in various preclinical models, and ii) anti-PRLR neutralizing antibodies that are currently in clinical Phase I for advanced breast and prostate cancers. The main purpose of this review is to discuss the multiple organs/diseases that may be considered as potential targets/indications for such inhibitors. This is done in light of reports suggesting that PRLR expression/signaling is increased in disease, and/or that systemic or locally elevated PRL levels correlate with (or promote) organ pathogenesis., Expert Opinion: The two immediate challenges in the field are i) to provide the scientific community with potent anti-prolactin receptor antibodies to map prolactin receptor expression in target organs, and ii) to take advantage of the availability of functionally validated PRLR blockers to establish the relevance of these potential indications in humans.
- Published
- 2015
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20. Prolactin-induced prostate tumorigenesis.
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Sackmann-Sala L and Goffin V
- Subjects
- Animals, Humans, Male, Mice, Prolactin pharmacology, Prostate drug effects, Prostatic Neoplasms therapy, Receptors, Androgen physiology, STAT5 Transcription Factor physiology, Carcinogenesis, Prolactin physiology, Prostate pathology, Prostatic Neoplasms pathology
- Abstract
The physiological role of prolactin (PRL) in the prostate gland is not clearly understood. Genetically-modified mouse models that have invalidated actors of the PRL signaling axis failed to identify an essential regulatory function on this tissue. However, a large body of evidence suggests an important role for PRL in prostate tumorigenesis. Mainly through the activation of its downstream target STAT5, PRL can induce growth and survival of prostate cancer cells and tissues in several experimental settings. In the clinic, PRL expression and STAT5 activation in human prostate tumors correlate with disease severity. Available data point to a role of local (autocrine/paracrine) rather than circulating (endocrine) PRL in the induction of disease progression. In mice, transgenic expression of PRL in the prostate leads to enhanced epithelial hyperplasia and dysplasia, with amplification of basal/stem cells which have been recently identified as prostate cancer-initiating cells. Thus, targeting PRL receptor (PRLR)/STAT5 signaling may provide an alternative therapy for the treatment of prostate cancer. Corresponding targeted therapies currently in preclinical development include antagonists or blocking antibodies for the PRLR and small molecule inhibitors directed against the tyrosine kinase JAK2 upstream of STAT5. Present efforts are aimed at validating these therapies for the treatment of prostate cancer, while understanding the mechanisms of disease progression induced by PRL/STAT5.
- Published
- 2015
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21. Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors.
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Sackmann-Sala L, Chiche A, Mosquera-Garrote N, Boutillon F, Cordier C, Pourmir I, Pascual-Mathey L, Kessal K, Pigat N, Camparo P, and Goffin V
- Subjects
- Animals, Carcinogenesis pathology, Cell Differentiation, Cell Proliferation, Male, Mice, Mice, Transgenic, Neoplastic Stem Cells, Prolactin genetics, Prostate pathology, Carcinogenesis metabolism, Prolactin metabolism, Prostate metabolism, STAT5 Transcription Factor metabolism, Signal Transduction physiology
- Abstract
Current androgen ablation therapies for prostate cancer are initially successful, but the frequent development of castration resistance urges the generation of alternative therapies and represents an important health concern. Prolactin/signal transducer and activator of transcription 5 (STAT5) signaling is emerging as a putative target for alternative treatment for prostate cancer. However, mechanistic data for its role in development or progression of prostate tumors are scarce. In vivo mouse studies found that local prolactin induced the amplification of prostate epithelial basal/stem cells. Because these cells are proposed cells of origin for prostate cancer and disease recurrence, we looked further into this amplification. Our results indicated that sustained Stat5 activation was associated with the occurrence of abnormal basal/stem cell clusters in prostate epithelium of prostate-specific prolactin-transgenic mice. Analysis of epithelial areas containing these clusters found high proliferation, Stat5 activation, and expression of stem cell antigen 1. Furthermore, enhanced prolactin signaling also led to amplification of a luminal cell population that was positive for stem cell antigen 1. These cells may originate from amplified basal/stem cells and might represent important progenitors for tumor development in prostate epithelium. These data provide a deeper understanding of the initial stages of prostate tumorigenesis induced by prolactin to help determine whether this hormone or its downstream messengers could be useful targets for prostate cancer treatment in the future.
- Published
- 2014
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22. Prolactin induces apoptosis of lactotropes in female rodents.
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Ferraris J, Zárate S, Jaita G, Boutillon F, Bernadet M, Auffret J, Seilicovich A, Binart N, Goffin V, and Pisera D
- Subjects
- Animals, Cell Proliferation drug effects, Down-Regulation drug effects, Estrous Cycle drug effects, Female, Gene Knockout Techniques, Lactotrophs metabolism, Mice, Prolactin metabolism, Rats, Receptors, Prolactin deficiency, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Signal Transduction drug effects, Apoptosis drug effects, Lactotrophs cytology, Lactotrophs drug effects, Prolactin pharmacology
- Abstract
Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGΔ1-9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result in pituitary hyperplasia and eventual prolactinoma development, as observed in TGΔ1-9-G129R-hPRL and PRLRKO mice, respectively.
- Published
- 2014
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23. Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner.
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Neradugomma NK, Subramaniam D, Tawfik OW, Goffin V, Kumar TR, Jensen RA, and Anant S
- Subjects
- Base Sequence, Colonic Neoplasms metabolism, DNA Primers, Humans, Phosphorylation, Polymerase Chain Reaction, Colonic Neoplasms pathology, Extracellular Signal-Regulated MAP Kinases metabolism, Janus Kinase 2 metabolism, Neoplastic Stem Cells metabolism, Prolactin metabolism, Receptors, Notch metabolism, STAT3 Transcription Factor metabolism, Signal Transduction
- Abstract
Prolactin (PRL) is a secretory cytokine produced by various tissues. Binding to the cognate PRL receptor (PRLR), it activates intracellular signaling via janus kinase (JAK), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) proteins. PRL regulates diverse activities under normal and abnormal conditions, including malignancies. Previous clinical data suggest serum PRL levels are elevated in colorectal cancer (CRC) patients. In this study, we first determined the expression of PRL and PRLR in colon cancer tissue and cell lines. Higher levels of PRLR expression were observed in the cancer cells and cell lines compared with normal colonic epithelial cells. Incubation of colon cancer cells with PRL-induced JAK2, STAT3 and ERK1/2 phosphorylation and increased expression of Jagged 1, which is a Notch-1 receptor ligand. Notch signaling regulates CRC stem cell population. We observed increased accumulation of the cleaved/active form of Notch-1 receptor (Notch intracellular domain) and increased expression of Notch responsive genes HEY1, HES1 and stem cell marker genes DCLK1, LGR5, ALDH1 and CD44. Finally, inhibiting PRL induced JAK2-STAT3 and JAK2-ERK1/2 using AG490 and PD98059, respectively, leads to complete abrogation of Notch signaling, suggesting a role for this pathway in regulating CRC stem cells. Together, our results demonstrate that cytokine signaling induced by PRL is active in colorectal cancers and may provide a novel target for therapeutic intervention.
- Published
- 2014
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24. Fetal pancreas transplants are dependent on prolactin for their development and prevent type 1 diabetes in syngeneic but not allogeneic mice.
- Author
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Fourcade G, Colombo BM, Grégoire S, Baeyens A, Rachdi L, Guez F, Goffin V, Scharfmann R, and Salomon BL
- Subjects
- Animals, Cell Differentiation, Crosses, Genetic, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 pathology, Female, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells cytology, Insulin-Secreting Cells immunology, Insulin-Secreting Cells metabolism, Insulin-Secreting Cells pathology, Islets of Langerhans Transplantation immunology, Islets of Langerhans Transplantation methods, Islets of Langerhans Transplantation pathology, Kidney, Male, Mice, Mice, Knockout, Mice, Nude, Mice, Transgenic, Pancreas Transplantation immunology, Pancreas Transplantation pathology, Sex Characteristics, Specific Pathogen-Free Organisms, Transplantation, Heterotopic immunology, Transplantation, Heterotopic pathology, Transplantation, Homologous, Transplantation, Isogeneic, Diabetes Mellitus, Type 1 prevention & control, Embryo, Mammalian, Fetus, Pancreas Transplantation methods, Prolactin therapeutic use, Transplantation, Heterotopic methods
- Abstract
Transplantation of adult pancreatic islets has been proposed to cure type 1 diabetes (T1D). However, it is rarely considered in the clinic because of its transient effect on disease, the paucity of donors, and the requirement for strong immunosuppressive treatment to prevent allogeneic graft rejection. Transplantation of fetal pancreases (FPs) may constitute an attractive alternative because of potential abundant donor sources, possible long-term effects due to the presence of stem cells maintaining tissue integrity, and their supposed low immunogenicity. In this work, we studied the capacity of early FPs from mouse embryos to develop into functional pancreatic islets producing insulin after transplantation in syngeneic and allogeneic recipients. We found that as few as two FPs were sufficient to control T1D in syngeneic mice. Surprisingly, their development into insulin-producing cells was significantly delayed in male compared with female recipients, which may be explained by lower levels of prolactin in males. Finally, allogeneic FPs were rapidly rejected, even in the context of minor histocompatibility disparities, with massive graft infiltration with T and myeloid cells. This work suggests that FP transplantation as a therapeutic option of T1D needs to be further assessed and would require immunosuppressive treatment.
- Published
- 2013
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25. Prolactin regulates transcription of the ion uptake Na+/Cl- cotransporter (ncc) gene in zebrafish gill.
- Author
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Breves JP, Serizier SB, Goffin V, McCormick SD, and Karlstrom RO
- Subjects
- Animals, Gene Expression Regulation drug effects, Gills drug effects, Prolactin pharmacology, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism, Sodium Chloride Symporters genetics, Transcription, Genetic drug effects, Water chemistry, Water-Electrolyte Balance drug effects, Zebrafish Proteins genetics, Gills metabolism, Ion Transport, Prolactin analogs & derivatives, Prolactin physiology, Sodium Chloride Symporters metabolism, Zebrafish metabolism, Zebrafish Proteins metabolism
- Abstract
Prolactin (PRL) is a well-known regulator of ion and water transport within osmoregulatory tissues across vertebrate species, yet how PRL acts on some of its target tissues remains poorly understood. Using zebrafish as a model, we show that ionocytes in the gill directly respond to systemic PRL to regulate mechanisms of ion uptake. Ion-poor conditions led to increases in the expression of PRL receptor (prlra), Na(+)/Cl(-) cotransporter (ncc; slc12a10.2), Na(+)/H(+) exchanger (nhe3b; slc9a3.2), and epithelial Ca(2+) channel (ecac; trpv6) transcripts within the gill. Intraperitoneal injection of ovine PRL (oPRL) increased ncc and prlra transcripts, but did not affect nhe3b or ecac. Consistent with direct PRL action in the gill, addition of oPRL to cultured gill filaments stimulated ncc in a concentration-dependent manner, an effect blocked by a pure human PRL receptor antagonist (Δ1-9-G129R-hPRL). These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl(-) uptake in zebrafish for the first time., (Copyright © 2013. Published by Elsevier Ireland Ltd.)
- Published
- 2013
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26. Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis.
- Author
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Ferraris J, Bernichtein S, Pisera D, and Goffin V
- Subjects
- Animals, Homeostasis drug effects, Humans, Pituitary Gland drug effects, Prolactin metabolism, Protein Binding drug effects, Protein Binding physiology, Receptors, Prolactin metabolism, Signal Transduction drug effects, Signal Transduction physiology, Homeostasis physiology, Pituitary Gland physiology, Prolactin physiology, Receptors, Prolactin antagonists & inhibitors
- Abstract
The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level., (© 2013 S. Karger AG, Basel.)
- Published
- 2013
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27. Meeting report: the 2012 FASEB Science Research Conference "The growth hormone/prolactin family in biology and disease" A novel biannual rendez-vous in the endocrinology landscape.
- Author
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Goffin V and Carter-Su C
- Subjects
- Biomedical Research, Congresses as Topic, Human Growth Hormone adverse effects, Human Growth Hormone therapeutic use, Humans, Prolactin adverse effects, Prolactin therapeutic use, Human Growth Hormone physiology, Prolactin physiology
- Abstract
The inaugural edition of the FASEB Science Research Conference entitled 'The GHIPRL Family in Biology and Disease' was held this past summer at Snowmass, Colorado. This report provides an overview of the scientific content and a taste of the atmosphere of this novel meetinq in the field of Endocrinology.
- Published
- 2012
28. Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?
- Author
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Reuwer AQ, Nowak-Sliwinska P, Mans LA, van der Loos CM, von der Thüsen JH, Twickler MT, Spek CA, Goffin V, Griffioen AW, and Borensztajn KS
- Subjects
- Angiogenesis Inducing Agents adverse effects, Animals, Breast Neoplasms pathology, Cell Line, Chick Embryo, Collagen metabolism, Drug Combinations, Endothelial Cells metabolism, Female, Immunohistochemistry, Laminin metabolism, MAP Kinase Signaling System drug effects, Mice, Phosphorylation, Proteoglycans metabolism, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism, STAT5 Transcription Factor genetics, STAT5 Transcription Factor metabolism, Endothelial Cells pathology, Neovascularization, Pathologic pathology, Prolactin adverse effects, Signal Transduction drug effects
- Abstract
Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Published
- 2012
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29. Prolactin receptor antagonism in mouse anterior pituitary: effects on cell turnover and prolactin receptor expression.
- Author
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Ferraris J, Boutillon F, Bernadet M, Seilicovich A, Goffin V, and Pisera D
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Cells, Cultured, Hormone Antagonists metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Organ Size, Pituitary Gland, Anterior cytology, Pituitary Gland, Anterior drug effects, Pituitary Gland, Anterior pathology, Prolactin antagonists & inhibitors, Prolactin genetics, Prolactin metabolism, Prolactin pharmacology, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin genetics, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Signal Transduction drug effects, Cell Proliferation drug effects, Gene Expression Regulation drug effects, Hormone Antagonists pharmacology, Pituitary Gland, Anterior metabolism, Prolactin analogs & derivatives, Prolactin physiology, Receptors, Prolactin metabolism
- Abstract
Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates in the control of anterior pituitary cell turnover. In the present study, we explored the action of prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression of the prolactin receptor. To determine the activity of endogenous prolactin, we evaluated the effect of the competitive prolactin receptor antagonist Δ1-9-G129R-hPRL in vivo, using transgenic mice that constitutively and systemically express this antagonist. The weight of the pituitary gland and the anterior pituitary proliferation index, determined by BrdU incorporation, were higher in transgenic mice expressing the antagonist than in wild-type littermates. In addition, blockade of prolactin receptor in vitro by Δ1-9-G129R-hPRL increased proliferation and inhibited apoptosis of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells, including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine antiproliferative and proapoptotic factor in the anterior pituitary gland. In addition, anterior pituitary expression of the long isoform of the prolactin receptor, measured by real-time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor antagonist, whereas only a modest increase in the S3 short-isoform expression was observed. These results suggest that endogenous prolactin may regulate its own biological actions in the anterior pituitary by inhibiting the expression of the long isoform of the prolactin receptor. In conclusion, our observations suggest that prolactin is involved in the maintenance of physiological cell renewal in the anterior pituitary. Alterations in this physiological role of prolactin could contribute to pituitary tumor development.
- Published
- 2012
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30. Prolactin regulation of the prostate gland: a female player in a male game.
- Author
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Goffin V, Hoang DT, Bogorad RL, and Nevalainen MT
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Female, Gene Targeting, Humans, Male, Prolactin biosynthesis, Prolactin deficiency, Prostate metabolism, Prostate pathology, Prostatic Neoplasms blood, Prostatic Neoplasms drug therapy, Receptors, Prolactin biosynthesis, Receptors, Prolactin deficiency, Receptors, Prolactin physiology, Signal Transduction drug effects, Signal Transduction genetics, Prolactin physiology, Prostate physiology, Prostatic Neoplasms metabolism
- Abstract
Prolactin is best known for its actions on the mammary gland. However, circulating prolactin is also detected in males and its receptor (PRLR) is expressed in the prostate, suggesting that the prostate is a target of prolactin. Germline knockout of prolactin or its receptor has failed to reveal a key role for prolactin signaling in mouse prostate physiology. However, several studies involving rodent models and human prostate cell lines and specimens have supported the contribution of the canonical PRLR-Jak2-Stat5a/b pathway to prostate cancer tumorigenesis and progression. Increased expression of prolactin in the prostate itself (rather than changes in circulating prolactin levels) and crosstalk with androgen receptor (AR) signaling are potential mechanisms for increased Stat5a/b signaling in prostate cancer. In the mouse prostate, prolactin overexpression results in disorganized expansion of the basal/stem cell compartment, which has been proposed to house putative prostate tumor-initiating cells. These findings provide new insight into the molecular and cellular targets by which locally produced prolactin could contribute to prostate cancer initiation and progression. A number of pharmacological inhibitors targeting various levels of the PRLR-Jak2-Stat5a/b pathway have been developed and are entering clinical trials for advanced prostate cancer.
- Published
- 2011
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31. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.
- Author
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Scotland PE, Patil M, Belugin S, Henry MA, Goffin V, Hargreaves KM, and Akopian AN
- Subjects
- Animals, Estradiol administration & dosage, Female, Freund's Adjuvant adverse effects, Humans, Inflammation chemically induced, Male, Ovariectomy, Patch-Clamp Techniques, Peripheral Nerves cytology, Peripheral Nerves metabolism, Rats, Rats, Sprague-Dawley, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism, Sensory Receptor Cells metabolism, TRPV Cation Channels metabolism, Hyperalgesia metabolism, Inflammation metabolism, Prolactin metabolism
- Abstract
Prolactin (PRL) is a hormone and a neuromodulator. It sensitizes TRPV1 (transient receptor potential cation channel subfamily V member 1) responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund's adjuvant (CFA) stimulates release of peripheral, but not systemic, PRL within 6-48 h in both ovariectomized females with estradiol replacement (OVX-E) and intact male rats. The time course of release varies in OVX-E and intact male rats. We next employed the prolactin receptor (PRL-R) antagonist Δ1-9-G129R-hPRL to assess the role of locally produced PRL in nociception. Applied at a ratio of 1 : 1 (PRL:Δ1-9-G129R-hPRL; 40 nm each), this antagonist was able to nearly (≈ 80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at 6 h but not at 24 h. In contrast, PRL contributed to inflammatory thermal hyperalgesia in intact male rats at 24, but not at 6 h. These findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Furthermore, PRL acts as an inflammatory mediator at different time points for female and intact male rats., (© 2011 UT Health Science Center San Antonio. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)
- Published
- 2011
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32. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding.
- Author
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Hansen MJ, Olsen JG, Bernichtein S, O'Shea C, Sigurskjold BW, Goffin V, and Kragelund BB
- Subjects
- Calorimetry, Circular Dichroism, Histidine chemistry, Histidine metabolism, Humans, Hydrogen-Ion Concentration, Models, Molecular, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Prolactin genetics, Protein Binding, Protein Conformation, Receptors, Prolactin chemistry, Receptors, Prolactin genetics, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Thermodynamics, Prolactin metabolism, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism
- Abstract
The cytokine hormone prolactin has a vast number of diverse functions. Unfortunately, it also exhibits tumor growth promoting properties, which makes the development of prolactin receptor antagonists a priority. Prolactin binds to its cognate receptor with much lower affinity at low pH than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ∼6.8 making histidine residues obvious candidates for examination. From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure antagonists were developed earlier and the histidine mutations were introduced within such background. The antagonistic properties were maintained and the high affinity at low pH conserved. The implications of these findings may open new areas of research in the field of prolactin cancer biology., (Copyright © 2010 John Wiley & Sons, Ltd.)
- Published
- 2011
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33. The prolactin receptor is expressed in macrophages within human carotid atherosclerotic plaques: a role for prolactin in atherogenesis?
- Author
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Reuwer AQ, van Eijk M, Houttuijn-Bloemendaal FM, van der Loos CM, Claessen N, Teeling P, Kastelein JJ, Hamann J, Goffin V, von der Thüsen JH, Twickler MT, and Aten J
- Subjects
- Computer Systems, Female, Humans, Immunohistochemistry, In Situ Hybridization, Inflammation etiology, Inflammation Mediators metabolism, Male, Microscopy, Immunoelectron, Polymerase Chain Reaction, Prolactin genetics, RNA, Messenger metabolism, Receptors, Prolactin genetics, Signal Transduction, Tissue Distribution, Atherosclerosis etiology, Carotid Artery Diseases metabolism, Carotid Artery Diseases pathology, Carotid Stenosis metabolism, Macrophages metabolism, Prolactin metabolism, Receptors, Prolactin metabolism
- Abstract
Atherosclerotic vascular disease is the consequence of a chronic inflammatory process, and prolactin has been shown to be a component of the inflammatory response. Additionally, recent studies indicate that prolactin contributes to an atherogenic phenotype. We hypothesized that this may be the result of a direct effect of prolactin on atherogenesis through activation of the prolactin receptor. Human carotid atherosclerotic plaques were obtained from patients by endarteriectomies. The mRNA of prolactin receptor, but not of prolactin, was detected in these atherosclerotic plaques by quantitative real-time PCR. In situ hybridization confirmed the expression of the prolactin receptor in mononuclear cells. Analysis at the protein level using immunohistochemistry and immunoelectron microscopy revealed that the prolactin receptor was abundantly present in macrophages near the lipid core and shoulder regions of the plaques. Our findings demonstrate that the prolactin receptor is present in macrophages of the atherosclerotic plaque at sites of most prominent inflammation. We therefore propose that prolactin receptor signaling contributes to the local inflammatory response within the atherosclerotic plaque and thus to atherogenesis.
- Published
- 2011
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34. Structural characterization of the stem-stem dimerization interface between prolactin receptor chains complexed with the natural hormone.
- Author
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van Agthoven J, Zhang C, Tallet E, Raynal B, Hoos S, Baron B, England P, Goffin V, and Broutin I
- Subjects
- Amino Acid Substitution, Crystallography, X-Ray, Models, Molecular, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Quaternary, Surface Plasmon Resonance, Prolactin chemistry, Prolactin metabolism, Protein Multimerization, Receptors, Prolactin chemistry, Receptors, Prolactin metabolism
- Abstract
The most promising approach to targeting the tumor-growth-promoting actions of prolactin (PRL) mediated by its autocrine/paracrine pathway has been the development of specific PRL receptor (PRLR) antagonists. However, the optimization of such antagonists requires a thorough understanding of the activation mechanism of PRLR. We have thus conducted a systematic X-ray crystallographic study in order to visualize the successive steps of PRLR activation by PRL. We report here the structure at 3.35 Å resolution of the 1:2 complex between natural PRL and two PRLR chains (PRLR1 and PRLR2), corresponding to the final activated state of PRLR. Further than our previously published structure involving an affinity-matured PRL variant, this structure allowed to visualize for the first time the loop L5 spanning PRLR2 residues Thr133-Phe140, revealing its central implication for the three intermolecular interfaces of the complex. We equally succeeded in obtaining a comprehensive picture of the PRLR-PRLR dimerization interface, also called stem-stem interface. Site-directed mutagenesis was conducted to probe the energetic importance of stem-stem contacts highlighted by the structure. Surprisingly, in spite of significant structural differences between the PRL/PRLR(2) complex and the 1:2 growth hormone/growth hormone receptor complex, our mutational data suggest that hot-spot residues that stabilize the receptor dimerization interface are equivalent in the two complexes. This study provides a new overall picture of the structural features of PRLR involved in stabilizing its complex with PRL., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
35. Prolactin: an emerging force along the cutaneous-endocrine axis.
- Author
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Langan EA, Foitzik-Lau K, Goffin V, Ramot Y, and Paus R
- Subjects
- Animals, Humans, Models, Biological, Prolactin classification, Prolactin genetics, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Skin cytology, Prolactin metabolism, Skin metabolism
- Abstract
Prolactin (PRL), one of the most diverse regulators in mammalian biology, is produced in both human skin and hair follicles. Important advances in our understanding of the intracutaneous regulation and functions of PRL have recently been made using the serum-free skin and hair follicle organ culture technique. Given that human skin is the largest peripheral endocrine organ and a key interface between the endocrine, nervous and immune systems, a detailed understanding of PRL in the cutaneous context promises to have far-reaching implications beyond the skin. The current review presents a timely cutaneous perspective on the production, regulation and functions of PRL and summarizes the key questions facing extrapituitary PRL research in general and cutaneous PRL research in particular., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
36. Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors.
- Author
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Rouet V, Bogorad RL, Kayser C, Kessal K, Genestie C, Bardier A, Grattan DR, Kelder B, Kopchick JJ, Kelly PA, and Goffin V
- Subjects
- Animals, Base Sequence, Cell Proliferation, DNA Primers genetics, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Neoplasms, Hormone-Dependent genetics, Neoplasms, Hormone-Dependent therapy, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Peptide Fragments genetics, Peptide Fragments metabolism, Prolactin genetics, Prostate metabolism, Prostate pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms therapy, Rats, Receptors, Prolactin antagonists & inhibitors, Recombinant Proteins genetics, Recombinant Proteins metabolism, STAT5 Transcription Factor metabolism, Signal Transduction, Tissue Distribution, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Prolactin metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology
- Abstract
Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1-positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Delta1-9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.
- Published
- 2010
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37. New concepts in prolactin biology.
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Bernichtein S, Touraine P, and Goffin V
- Subjects
- Animals, Breast Neoplasms blood, Breast Neoplasms epidemiology, Dopamine, Female, Humans, Hyperprolactinemia, Male, Mutation, Prolactin chemistry, Prolactin genetics, Prostatic Neoplasms, Receptors, Prolactin chemistry, Receptors, Prolactin genetics, Receptors, Prolactin metabolism, Risk Factors, STAT5 Transcription Factor, Prolactin physiology
- Abstract
Human prolactin (PRL) is currently viewed as a hormone of pituitary origin, whose production (i.e. serum levels) is controlled by dopamine, whose biological actions relate exclusively to lactation and reproductive functions, for which any genetic disorder is yet to be identified, and whose unique associated pathology is hyperprolactinemia. Both experimental studies and human sample/cohort-based investigations performed during the past decade have considerably widened our perception of PRL biology: i) there are now strong epidemiological arguments supporting the fact that circulating PRL is a risk factor for breast cancer, ii) in addition to the endocrine hormone, locally produced PRL has been documented in several human tissues; there is increasing evidence supporting the tumor growth potency of local PRL, acting via autocrine/paracrine mechanisms, in both rodent models, and human breast and prostate tumors, iii) the first functional germinal polymorphisms of the PRL receptor were recently identified in patients presenting with breast tumors, which involve single amino acid substitution variants exhibiting constitutive activity, iv) human PRL analogs have been engineered, which were shown in experimental models to down-regulate the effects triggered by local PRL (competitive antagonism) or by the constitutively active receptor variants (inverse agonism). The aim of this review is to discuss these novel concepts in PRL biology, including their potential pathophysiological outcomes.
- Published
- 2010
- Full Text
- View/download PDF
38. Prolactin--a novel neuroendocrine regulator of human keratin expression in situ.
- Author
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Ramot Y, Bíró T, Tiede S, Tóth BI, Langan EA, Sugawara K, Foitzik K, Ingber A, Goffin V, Langbein L, and Paus R
- Subjects
- Adult, Aged, Blotting, Western, Female, Gene Expression Profiling, Hair Follicle metabolism, Humans, Immunoenzyme Techniques, Keratinocytes metabolism, Keratins genetics, Middle Aged, Oligonucleotide Array Sequence Analysis, Organ Culture Techniques, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Biomarkers metabolism, Hair Follicle drug effects, Keratinocytes drug effects, Keratins metabolism, Prolactin pharmacology
- Abstract
The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ-cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin-associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. PRL also up-regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that "tonic stimulation" by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ.
- Published
- 2010
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- View/download PDF
39. Crystal structure of an affinity-matured prolactin complexed to its dimerized receptor reveals the topology of hormone binding site 2.
- Author
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Broutin I, Jomain JB, Tallet E, van Agthoven J, Raynal B, Hoos S, Kragelund BB, Kelly PA, Ducruix A, England P, and Goffin V
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Crystallography, Dimerization, Drug Design, Glycine metabolism, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Placental Lactogen chemistry, Placental Lactogen genetics, Prolactin metabolism, Protein Structure, Secondary, Protein Structure, Tertiary, Rats, Receptors, Prolactin metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Sheep, Structure-Activity Relationship, Surface Plasmon Resonance, X-Ray Diffraction, Prolactin chemistry, Prolactin genetics, Receptors, Prolactin chemistry, Receptors, Prolactin genetics
- Abstract
We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely related PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL.PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural components of PRL site 2 ("three-pin plug"): the conserved glycine 129 of helix alpha3, the hydrogen bond network involving surrounding residues (glycine cavity), and the N terminus. The model provides a molecular basis for the properties of the different PRL analogs designed to date, including PRLR antagonists. Finally, comparison of our 1:2 PRL.PRLR(2) structure with those of free PRL and its 1:1 complex indicates that the structure of PRL undergoes significant changes when binding the first, but not the second receptor. This suggests that the second PRLR moiety adapts to the 1:1 complex rather than the opposite. In conclusion, this structure will be a useful guiding tool for further investigations of the molecular mechanisms involved in PRLR dimerization and activation, as well as for the optimization of PRLR antagonists, an emerging class of compounds with high therapeutic potential against breast and prostate cancer.
- Published
- 2010
- Full Text
- View/download PDF
40. Mind the (gender) gap: does prolactin exert gender and/or site-specific effects on the human hair follicle?
- Author
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Langan EA, Ramot Y, Goffin V, Griffiths CE, Foitzik K, and Paus R
- Subjects
- Animals, Female, Humans, Male, Hair Follicle growth & development, Hair Follicle physiology, Prolactin physiology, Sex Characteristics
- Published
- 2010
- Full Text
- View/download PDF
41. Prolactin levels and the risk of future coronary artery disease in apparently healthy men and women.
- Author
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Reuwer AQ, Twickler MT, Hutten BA, Molema FW, Wareham NJ, Dallinga-Thie GM, Bogorad RL, Goffin V, Smink-Bol M, Kastelein JJ, Boekholdt SM, and Khaw KT
- Subjects
- Aged, Atherosclerosis pathology, Case-Control Studies, Cohort Studies, Coronary Vessels pathology, Female, Humans, Male, Middle Aged, Odds Ratio, Receptors, Prolactin metabolism, Risk Factors, Coronary Artery Disease epidemiology, Prolactin blood
- Abstract
Background: Prolactin is increasingly recognized to play a stimulatory role in the inflammatory response. Because inflammation is considered of crucial importance in the development of atherosclerosis, we aimed to evaluate whether prolactin levels are associated with the occurrence of coronary artery disease (CAD)., Methods and Results: We performed a nested case-control study in the prospective EPIC-Norfolk cohort. Cases were apparently healthy men and women, aged 45 to 79 years, who developed fatal or nonfatal CAD (n=882). Controls remained free of CAD (n=1490). Overall, systemic prolactin levels did not differ between cases and controls, and people in the highest prolactin tertile did not have a significantly increased risk of developing future CAD (in men, odds ratio, 1.21; 95% CI, 0.92 to 1.61; in women, odds ratio, 1.12; 95% CI, 0.76 to 1.64). However, in a separate immunohistochemical study, the presence of prolactin receptors could be demonstrated in postmortem human coronary artery plaques (preliminary data)., Conclusions: Elevated systemic prolactin levels do not predict CAD in the general population. However, prolactin receptors were found in human coronary artery plaques. This observation may indicate a role of prolactin within atherosclerotic plaques. More studies are needed to define the possible role of prolactin in atherosclerotic plaque development.
- Published
- 2009
- Full Text
- View/download PDF
42. Prolactin does not affect human platelet aggregation or secretion.
- Author
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Reuwer AQ, Nieuwland R, Fernandez I, Goffin V, van Tiel CM, Schaap MC, Berckmans RJ, Kastelein JJ, and Twickler MT
- Subjects
- Adenosine Diphosphate metabolism, Allosteric Regulation, Blood Platelets pathology, Cell Line, Cell Separation, Dual Specificity Phosphatase 2 metabolism, Flow Cytometry, Gene Expression Regulation, Humans, Male, P-Selectin metabolism, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Protein Binding, Receptors, Prolactin genetics, Transfection, Blood Platelets metabolism, Platelet Aggregation genetics, Prolactin metabolism, Receptors, Prolactin metabolism
- Abstract
Platelets play an important role in the development of plaque formation and in the events after rupture of the atherosclerotic plaque, leading to atherothrombosis. Multiple hormones, either in excess or when deficient, are involved in the development of atherothrombotic disease, but, to which extent such hormones affect platelet function, is still controversial. It was the objective of this study to assess the ability of the pituitary hormone prolactin to affect platelet functions. Venous blood was collected from six healthy males. Platelet activation was studied by (i) flow cytometry in whole blood (exposure of P-selectin as a measure of platelet secretion, and binding of PAC-1 as a measure of ligand-binding conformation of alpha(IIb)beta(3)), and by (ii) optical aggregation and whole blood aggregation. All studies were performed without and with exposure to several concentrations of ADP (0.1, 0.5 and 1.0 microM) and prolactin (50 and 1,000 microg/l). The presence of the prolactin receptor was investigated by Western blot and flow cytometry. In response to either 50 or 1,000 microg/l prolactin, no evidence of platelet activation or aggregation was found. In addition, ADP-induced platelet activation or aggregation was not enhanced by prolactin. Finally, prolactin receptors could not be detected on the surface of platelets. The present data indicate that prolactin does not directly modulate platelet function.
- Published
- 2009
43. Rational design of competitive prolactin/growth hormone receptor antagonists.
- Author
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Tallet E, Rouet V, Jomain JB, Kelly PA, Bernichtein S, and Goffin V
- Subjects
- Animals, Binding Sites, Humans, Mutation genetics, Receptors, Prolactin chemistry, Receptors, Prolactin genetics, Drug Design, Prolactin metabolism, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism, Receptors, Somatotropin antagonists & inhibitors, Receptors, Somatotropin metabolism
- Abstract
There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.
- Published
- 2008
- Full Text
- View/download PDF
44. Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2.
- Author
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Swaminathan G, Varghese B, Thangavel C, Carbone CJ, Plotnikov A, Kumar KG, Jablonski EM, Clevenger CV, Goffin V, Deng L, Frank SJ, and Fuchs SY
- Subjects
- Catalysis, Cell Line, Endocytosis drug effects, Enzyme Activation physiology, Humans, Janus Kinase 2 deficiency, Ligands, Phosphorylation drug effects, Prolactin pharmacology, Receptors, Prolactin antagonists & inhibitors, Ubiquitination drug effects, Endocytosis physiology, Janus Kinase 2 metabolism, Prolactin physiology, Receptors, Prolactin metabolism, Ubiquitination physiology
- Abstract
Prolactin (PRL) activates its receptor to initiate signal transduction pathways (including activation of Janus kinases, Jak) but also stimulates downregulation of this receptor to limit the magnitude and duration of signaling. Degradation of the long form of PRL receptor (PRLr) depends on its phosphorylation on Ser349 that is required to facilitate PRLr ubiquitination. Signaling events that mediate PRL-induced degradation of PRLr remain to be elucidated. Here, we investigated the role of Jak2 activity in ligand-triggered increase of PRLr phosphorylation on Ser349, PRLr ubiquitination, endocytosis, and degradation. Using Jak2 reconstitution in Jak2-null cells as well as pharmacologic approaches, we found that treatment with PRL (but not with PRLr antagonist) promotes phosphorylation of PRLr on Ser349 and accelerates endocytosis of PRLr. Furthermore, PRL-stimulated PRLr phosphorylation, endocytosis, and degradation in Jak2-null cells reconstituted with wild type but not with catalytically inactive Jak2. We discuss how Jak2-mediated signaling might be transduced into Ser349 phosphorylation of PRLr as well as its ubiquitination and endocytosis.
- Published
- 2008
- Full Text
- View/download PDF
45. Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL.
- Author
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Jomain JB, Tallet E, Broutin I, Hoos S, van Agthoven J, Ducruix A, Kelly PA, Kragelund BB, England P, and Goffin V
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Circular Dichroism, Crystallography, X-Ray, Glycine genetics, Glycine metabolism, Hot Temperature, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Mutation genetics, Prolactin genetics, Protein Binding, Protein Denaturation, Protein Structure, Tertiary, Rats, Receptors, Prolactin chemistry, Structural Homology, Protein, Thermodynamics, Drug Design, Prolactin chemistry, Prolactin metabolism, Receptors, Prolactin antagonists & inhibitors, Receptors, Prolactin metabolism
- Abstract
Competitive antagonists of the human prolactin (hPRL) receptor are a novel class of molecules of potential therapeutic interest in the context of cancer. We recently developed the pure antagonist Del1-9-G129R-hPRL by deleting the nine N-terminal residues of G129R-hPRL, a first generation partial antagonist. We determined the crystallographic structure of Del1-9-G129R-hPRL, which revealed no major change compared with wild type hPRL, indicating that its pure antagonistic properties are intrinsically due to the mutations. To decipher the molecular bases of pure antagonism, we compared the biological, physicochemical, and structural properties of numerous hPRL variants harboring N-terminal or Gly(129) mutations, alone or combined. The pure versus partial antagonistic properties of the multiple hPRL variants could not be correlated to differences in their affinities toward the hPRL receptor, especially at site 2 as determined by surface plasmon resonance. On the contrary, residual agonism of the hPRL variants was found to be inversely correlated to their thermodynamic stability, which was altered by all the Gly(129) mutations but not by those involving the N terminus. We therefore propose that residual agonism can be abolished either by further disrupting hormone site 2-receptor contacts by N-terminal deletion, as in Del1-9-G129R-hPRL, or by stabilizing hPRL and constraining its intrinsic flexibility, as in G129V-hPRL.
- Published
- 2007
- Full Text
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46. Elevated serum bioactive prolactin concentrations in patients with systemic lupus erythematosus are associated with disease activity as disclosed by homologous receptor bioassays.
- Author
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Cárdenas-Mondragón G, Ulloa-Aguirre A, Isordia-Salas I, Goffin V, and Leaños-Miranda A
- Subjects
- Adult, Animals, Biological Assay, Cell Line, Tumor, Cell Proliferation drug effects, Female, Health Status, Humans, Lupus Erythematosus, Systemic physiopathology, Male, Mice, Prolactin pharmacology, Rats, Receptors, Prolactin genetics, Severity of Illness Index, Lupus Erythematosus, Systemic blood, Prolactin blood, Receptors, Prolactin metabolism
- Abstract
Objective: To assess the bioactivity of circulating prolactin (PRL) in serum samples from patients with systemic lupus erythematosus (SLE) using 2 novel homologous in vitro bioassays, and to correlate PRL bioactivity with lupus activity., Methods: Serum samples from 98 SLE patients with and without disease activity were tested for immunoreactive and bioactive concentrations of PRL., Results: Patients with active disease exhibited higher bioactive serum PRL levels in homologous bioassays (p
- Published
- 2007
47. Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway.
- Author
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Dagvadorj A, Collins S, Jomain JB, Abdulghani J, Karras J, Zellweger T, Li H, Nurmi M, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Goffin V, and Nevalainen MT
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunoblotting, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 genetics, Male, Mice, Mice, Nude, Neoplasm Metastasis, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Oligodeoxyribonucleotides, Antisense genetics, Phosphorylation drug effects, Prolactin antagonists & inhibitors, Prolactin genetics, Promoter Regions, Genetic genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor genetics, Signal Transduction genetics, Transcription, Genetic drug effects, Transplantation, Heterologous, Tumor Suppressor Proteins, Tyrphostins pharmacology, Janus Kinase 2 metabolism, Prolactin metabolism, Prostatic Neoplasms pathology, STAT5 Transcription Factor metabolism, Signal Transduction physiology
- Abstract
The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Delta1-9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.
- Published
- 2007
- Full Text
- View/download PDF
48. Autocrine prolactin inhibits human uterine decidualization: a novel role for prolactin.
- Author
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Eyal O, Jomain JB, Kessler C, Goffin V, and Handwerger S
- Subjects
- Blotting, Western, Caspase 3 biosynthesis, Caspase 3 genetics, Decidua drug effects, Decorin, Extracellular Matrix Proteins biosynthesis, Extracellular Matrix Proteins genetics, Fas Ligand Protein biosynthesis, Fas Ligand Protein genetics, Female, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Insulin-Like Growth Factor Binding Protein 1 biosynthesis, Insulin-Like Growth Factor Binding Protein 1 genetics, Laminin biosynthesis, Laminin genetics, Left-Right Determination Factors, Prolactin antagonists & inhibitors, Prolactin pharmacology, Proteoglycans biosynthesis, Proteoglycans genetics, RNA biosynthesis, RNA genetics, Receptors, Prolactin drug effects, Reverse Transcriptase Polymerase Chain Reaction, Transforming Growth Factor beta biosynthesis, Transforming Growth Factor beta genetics, Uterus drug effects, Autocrine Communication physiology, Decidua physiology, Prolactin physiology, Uterus physiology
- Abstract
Human prolactin (PRL) and its receptor (PRLR) are markedly induced during human uterine decidualization, and large amounts of PRL are released by decidual cells as differentiation progresses. However, the role of PRL in decidualization is unknown. In order to determine whether PRL plays an autocrine role in decidualization, human uterine fibroblast cells that were decidualized in vitro with medroxyprogestrerone acetate (1 microM), estradiol (10 nM), and prostaglandin E(2) (1 microM) were exposed to exogenous PRL and/or the pure PRLR antagonist delta1-9-G129R-PRL. As measured by quantitative PCR, cells that were decidualized in the presence of exogenous PRL (0.25-2 microg/ml) expressed significantly lower levels of mRNA for the genes that encode insulin-like growth factor binding protein 1 (IGFBP1), left-right determination factor 2 (LEFTY2), PRL, decorin (DCN), and laminin alpha 1 (LAMA1), all of which are known to be induced during decidualization. These effects were blocked when the cells were exposed simultaneously to PRL and the PRLR antagonist, which confirms the specific inhibitory action of PRL on the expression of decidualization markers. In addition, cells exposed to the PRLR antagonist alone expressed higher levels of the marker gene mRNAs than cells that were decidualized in control media. Taken together, these results strongly suggest that PRL acts via an autocrine mechanism to regulate negatively the extent of differentiation (decidualization) of human uterine cells.
- Published
- 2007
- Full Text
- View/download PDF
49. Prolactin stimulates prostate cell proliferation by increasing endoplasmic reticulum content due to SERCA 2b over-expression.
- Author
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Crépin A, Bidaux G, Vanden-Abeele F, Dewailly E, Goffin V, Prevarskaya N, and Slomianny C
- Subjects
- Calcium metabolism, Cell Line, Gene Expression Regulation, Enzymologic drug effects, Humans, Male, Prostate cytology, Prostate enzymology, RNA, Small Interfering genetics, Transfection, Cell Division drug effects, Endoplasmic Reticulum enzymology, Prolactin pharmacology, Prostate physiology, Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics
- Abstract
Prolactin (PRL) has been shown to be involved in the differentiation and proliferation of numerous tissues, including the prostate gland. Moreover, variations in [Ca2+]ER (calcium concentration within the endoplasmic reticulum) may play a role in cell growth. However, few studies have focused on the regulation of calcium homoeostasis by prolactin. The present study evaluates the regulation of calcium pools as well as the possible role of [Ca2+]ER variations as a signal for growth modulation by PRL. We show that PRL stimulates the proliferation of normal SV40 immortalized epithelial prostate (PNT1A) cells with a maximum effect at a dose of 100 ng/ml. We also show that 100 ng/ml PRL increases the [Ca2+]ER when measured either by indirect quantification with Fura-2AM after application of 1 mM thapsigargin or by direct quantification with Mag-Fura-2AM within the endoplas-mic reticulum. Western blot analysis shows that the SERCA 2b (sarcoendoplasmic calcium ATPase 2b) is over-expressed in PNT1A cells treated with 100 ng/ml PRL for 24 h. A small inter-fering RNA SERCA 2a/b, used to down-regulate endogenous SERCA 2b expression, reduced both PNT1A cell proliferation and [Ca2+]ER. We thus identify [Ca2+]ER and SERCA 2b as protagonists in PRL-induced proliferation.
- Published
- 2007
- Full Text
- View/download PDF
50. A new mechanism for prolactin processing into 16K PRL by secreted cathepsin D.
- Author
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Piwnica D, Fernandez I, Binart N, Touraine P, Kelly PA, and Goffin V
- Subjects
- Animals, Cells, Cultured, Culture Media, Conditioned, Hydrogen-Ion Concentration, Mice, Mice, Knockout, Models, Biological, Mutation, Proton-Translocating ATPases antagonists & inhibitors, Receptors, Prolactin genetics, Sodium-Hydrogen Exchangers antagonists & inhibitors, Tissue Distribution, Cathepsin D metabolism, Lysosomes enzymology, Prolactin metabolism, Proton-Translocating ATPases metabolism, Receptors, Prolactin metabolism, Sodium-Hydrogen Exchangers metabolism
- Abstract
Cathepsins are lysosomal enzymes that were shown to release the antiangiogenic fragments 16K prolactin (PRL), endostatin, and angiostatin by processing precursors at acidic pH in vitro. However, the physiological relevance of these findings is questionable because the neutral pH of physiological fluids is not compatible with the acidic conditions required for the proteolytic activity of these enzymes. Here we show that cathepsin D secreted from various tissues is able to process PRL into 16K PRL outside the cell. To specifically target extracellular proteolysis, we used tissues from PRL receptor-deficient mice, which are unable to internalize PRL. As assessed by the use of specific inhibitors of proton extruders, we show that the proteolytic activity of cathepsin D requires local acid secretion driven by Na(+)/H(+) exchangers and H(+)/ATPase. Although it is usually assumed that cathepsin-mediated generation of antiangiogenic peptides occurs in the moderately acidic pericellular milieu found in malignant tumors, we propose a new mechanism explaining the extracellular activity of this acidic protease under physiological pH. Our data support the concept that secreted lysosomal enzymes could be involved in the maintenance of angiogenesis dormancy via the generation of active antiangiogenic peptides in nonpathological contexts.
- Published
- 2006
- Full Text
- View/download PDF
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