160 results on '"Raul M. Luque"'
Search Results
102. Presence and clinical-histological correlates of ghrelin and somatostatin systems components in gastroenteropancreatic neuroendocrine tumors and lung carcinoids
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Rafael Sánchez-Sánchez, Justo P. Castaño, Aura D. Herrera-Martinez, Raul M Luque, Maria Angeles Galvez Moreno, Juan Salvatierra, Rosa Ortega Salas, Manuel D. Gahete, and Raquel Serrano Blanch
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medicine.medical_specialty ,Pathology ,Endocrinology ,Somatostatin ,Lung ,medicine.anatomical_structure ,business.industry ,Internal medicine ,medicine ,Ghrelin ,Neuroendocrine tumors ,business ,medicine.disease - Published
- 2016
103. Metformin suppressed the proliferation of prostate cancer cells in vitro and reduced prostate tumor growth in vivo under low-fat and, especially, under high-fat fed conditions
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Fernando Lopez-Lopez, Raul M Luque, Andre Sarmento-Cabral, and Justo P. Castaño
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medicine.medical_specialty ,business.industry ,medicine.disease ,In vitro ,High fat fed ,Metformin ,Prostate cancer ,medicine.anatomical_structure ,Endocrinology ,Prostate ,In vivo ,Internal medicine ,medicine ,Tumor growth ,business ,medicine.drug - Published
- 2016
104. Truncated sst5 receptor variants in pituitary tumors and cancer
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Raul M Luque, Alejandro Ibáñez-Costa, Justo P. Castaño, and Manuel D. Gahete
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business.industry ,Pituitary tumors ,Cancer research ,Medicine ,Cancer ,business ,medicine.disease ,Receptor - Published
- 2016
105. Functional role of somatostatin receptor subtype 1 (sst1) in prostate cancer: an in vitro approach
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Justo P. Castaño, Daniel Hormaechea-Agulla, Raul M Luque, Luke A. Selth, and Sergio Pedraza-Arevalo
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Functional role ,medicine.medical_specialty ,business.industry ,Somatostatin receptor ,medicine.disease ,In vitro ,Prostate cancer ,Endocrinology ,Internal medicine ,Cancer research ,Medicine ,Somatostatin receptor 2 ,Somatostatin receptor 1 ,business - Published
- 2016
106. LRP10, PGK1 and RPLP0: Best Reference Genes in Periprostatic Adipose Tissue under Obesity and Prostate Cancer Conditions
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Jesús M. Pérez-Gómez, Francisco Porcel-Pastrana, Marina De La Luz-Borrero, Antonio J. Montero-Hidalgo, Enrique Gómez-Gómez, Aura D. Herrera-Martínez, Rocío Guzmán-Ruiz, María M. Malagón, Manuel D. Gahete, and Raúl M. Luque
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periprostatic adipose tissue (PPAT) ,gene expression analysis ,reference genes ,RT-qPCR ,prostate cancer (PCa) ,weight-related disorders ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Obesity (OB) is a metabolic disorder characterized by adipose tissue dysfunction that has emerged as a health problem of epidemic proportions in recent decades. OB is associated with multiple comorbidities, including some types of cancers. Specifically, prostate cancer (PCa) has been postulated as one of the tumors that could have a causal relationship with OB. Particularly, a specialized adipose tissue (AT) depot known as periprostatic adipose tissue (PPAT) has gained increasing attention over the last few years as it could be a key player in the pathophysiological interaction between PCa and OB. However, to date, no studies have defined the most appropriate internal reference genes (IRGs) to be used in gene expression studies in this AT depot. In this work, two independent cohorts of PPAT samples (n = 20/n = 48) were used to assess the validity of a battery of 15 literature-selected IRGs using two widely used techniques (reverse transcription quantitative PCR [RT-qPCR] and microfluidic-based qPCR array). For this purpose, ΔCt method, GeNorm (v3.5), BestKeeper (v1.0), NormFinder (v.20.0), and RefFinder software were employed to assess the overall trends of our analyses. LRP10, PGK1, and RPLP0 were identified as the best IRGs to be used for gene expression studies in human PPATs, specifically when considering PCa and OB conditions.
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- 2023
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107. Abstract 2452: Dysregulated expression of the human long noncoding RNA GHSROS may influence prostate cancer progression and resistance to docetaxel
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Patrick Thomas, Eliza Whiteside, Gahete D. Manuel, Raul M Luque, Jennifer H. Gunter, Penny L. Jeffery, Adrian C. Herington, Carina Walpole, Colleen C. Nelson, Inge Seim, Lisa K. Chopin, Michelle Maugham, Rakesh N. Veedu, and Elizabeth D. Williams
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Cancer Research ,Prostate cancer ,Oncology ,Docetaxel ,business.industry ,medicine ,Cancer research ,medicine.disease ,business ,medicine.drug - Abstract
Long noncoding RNAs (lncRNAs) play key regulatory roles in cancer progression and are novel therapeutic targets. We recently discovered the lncRNA gene, GHSROS (GHSR opposite strand), on the antisense DNA strand of the ghrelin receptor gene (GHSR). Here, we studied the expression and function of GHSROS in prostate cancer. Interrogation of microarray and RNA-seq data sets revealed that (similar to other lncRNA oncogenes) GHSROS is actively transcribed, although expressed at very low levels in cancer cell lines and tissues. By quantitative RT-PCR we demonstrate that GHSROS is highly expressed in a subset of high-grade prostate cancers (~11.4%). Moreover, the lncRNA is upregulated in high Gleason-score prostate tumors in two clinical data sets. Forced GHSROS overexpression significantly increased in vitro cell proliferation and migration of PC3, DU145, and LNCaP prostate cancer cell lines (P ≤ 0.05, Student's t-test). Increased cell proliferation observed in GHSROS-overexpressing prostate cancer cell lines was recapitulated in PC3, DU145, and LNCaP prostate cancer xenografts in NOD/SCID mice. Cell survival was significantly increased in GHSROS-overexpressing LNCaP cells treated with the cytotoxic drug docetaxel (P ≤ 0.05, Student's t-test). Docetaxel treatment also increased GHSROS expression in native LNCaP and PC3 cells in a dose-dependent manner (P ≤ 0.05, Student's t-test). These data suggest that GHSROS mediates tumor survival and resistance to docetaxel. To identify fundamental drivers of the observed tumorigenic phenotype of GHSROS-overexpressing cell lines, high-throughput RNA-seq data from in vitro cultured PC3 cells and LNCaP xenografts were examined. A quarter of the genes differentially expressed by GHSROS-overexpressing PC3 cells were also differentially expressed by GHSROS-overexpressing LNCaP xenografts. These 101 genes include several transcription factors with established roles in prostate cancer (including the androgen receptor) and genes associated with metastasis and poor prognosis. Finally, we developed two distinct antisense oligonucleotides (ASOs) targeting GHSROS, achieving >60% knockdown, and their function was assessed in vitro. ASO inhibition of GHSROS expression reciprocally regulated cell growth and migration and the expression of a range of genes. These ASOs are currently being assessed in preclinical animal models. Our findings suggest that the long noncoding RNA GHSROS reprograms prostate cancer cells toward a more aggressive phenotype and that the lncRNA represents a promising therapeutic target. Citation Format: Patrick B. Thomas, Penny L. Jeffery, Gahete D. Manuel, Eliza J. Whiteside, Michelle Maugham, Carina Walpole, Jennifer H. Gunter, Elizabeth D. Williams, Colleen C. Nelson, Adrian C. Herington, Raul M. Luque, Rakesh N. Veedu, Lisa K. Chopin, Inge Seim. Dysregulated expression of the human long noncoding RNA GHSROS may influence prostate cancer progression and resistance to docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2452.
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- 2018
108. Diagnostic accuracy of MRI-Transrectal Ultrasound Fusion prostate Biopsy in men with previous prostate biopsies: Preliminary results of the FUPROS16 project
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Julia Carrasco-Valiente, E. Gómez Gómez, J. Valero Rosa, D. Lopez Ruiz, Raul M Luque, M.J. Requena Tapia, Ana Blanca, J.P. Campos Hernández, F. Triviño, and F.J. Anglada-Curado
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medicine.medical_specialty ,medicine.anatomical_structure ,Prostate biopsy ,medicine.diagnostic_test ,Prostate ,business.industry ,Urology ,Ultrasound ,medicine ,Diagnostic accuracy ,Radiology ,business - Published
- 2017
109. Expression of ghrelin and somatostatin systems components in pancreatic neuroendocrine tumours and their relationship with clinical-histological characteristics
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Raquel Serrano Blanch, Teresa Caro Cuenca, Manuel D. Gahete, Maria Angeles Galvez Moreno, Rafael Sánchez-Sánchez, Justo P. Castaño, Aura D. Herrera-Martinez, and Raul M Luque
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medicine.medical_specialty ,Somatostatin ,Endocrinology ,business.industry ,Internal medicine ,Medicine ,Somatostatin receptor 2 ,Ghrelin ,business - Published
- 2015
110. Presence and functional actions of In1-ghrelin splicing variant reveals a potentially relevant pathophysiological role in human pituitary adenomas
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Miguel A. Japón, Carlos Dieguez, Michael D. Culler, Jennifer Morgan, Esther Rivero-Cortés, Manuel Beltran, la Riva Andres de, Richard Nelson, Natia Tsomaia, Justo P. Castaño, Alfonso Soto-Moreno, María Ángeles Gálvez, Raul M Luque, David Rincón-Fernández, Manuel D. Gahete, Alejandro Ibáñez-Costa, Eva Venegas-Moreno, and Juan Garcia-Arnes
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RNA splicing ,Ghrelin ,Biology ,Bioinformatics ,Pathophysiology - Published
- 2015
111. The dopastatin BIM-23A760 distinctly influences key functional endpoints in different types of pituitary adenomas and normal pituitaries: role of somatostatin and dopamine receptor profile
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la Riva Andres de, Alberto Moreno-Carazo, Raul M Luque, Michael D. Culler, Luis Jiménez-Reina, Silvia Maraver-Selfa, Eva Venegas-Moreno, Alejandro Ibáñez-Costa, Alfonso Soto-Moreno, Rhonda D Kineman, Miguel A. Japón, Laura M. López-Sánchez, Susan M. Webb, Juan Garcia-Arnes, María Ángeles Gálvez, Francisco J Tinahones, Esther Rivero-Cortés, Justo P. Castaño, Mari C Vázquez-Borrego, and Manuel D. Gahete
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medicine.medical_specialty ,Endocrinology ,Somatostatin ,Dopamine receptor ,Dopastatin ,Internal medicine ,medicine ,Somatostatin receptor 2 ,Biology - Published
- 2015
112. Not so giants: mice lacking both somatostatin and cortistatin have high GH levels, but show no changes in growth rate or IGF-I levels
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Jose Cordoba-Chacon, Raul M Luque, Justo P. Castaño, Manuel D. Gahete, Sergio Pedraza-Arevalo, Fernando L-López, Ana I. Pozo-Salas, and Lecea Luis de
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medicine.medical_specialty ,Somatostatin ,Endocrinology ,Internal medicine ,medicine ,Biology ,Cortistatin - Published
- 2015
113. Associations between radiological parameters and molecular phenotype in human GH-secreting pituitary tumours: could they help in predicting the appropriate medical therapy?
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Raul M Luque-Huertas, Maria Rosa Alhambra-Exposito, Maria Sagrario Lombardo-Galera, María A Gálvez-Moreno, Justo Castano-Pastor, Manuel D. Gahete, Alejandro Ibáñez-Costa, and Esther Rivero-Cortés
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Pathology ,medicine.medical_specialty ,business.industry ,Radiological weapon ,Molecular phenotype ,medicine ,business ,Medical therapy ,Pituitary tumours - Published
- 2015
114. Dysregulation of the miRNome unveils a crosstalk between obesity and prostate cancer: miR-107 asa personalized diagnostic and therapeutic tool
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Vicente Herrero-Aguayo, Prudencio Sáez-Martínez, Juan M. Jiménez-Vacas, M. Trinidad Moreno-Montilla, Antonio J. Montero-Hidalgo, Jesús M. Pérez-Gómez, Juan L. López-Canovas, Francisco Porcel-Pastrana, Julia Carrasco-Valiente, Francisco J. Anglada, Enrique Gómez-Gómez, Elena M. Yubero-Serrano, Alejandro Ibañez-Costa, Aura D. Herrera-Martínez, André Sarmento-Cabral, Manuel D. Gahete, and Raúl M. Luque
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miRNome ,miR-107 ,prostate cancer ,obesity ,non-invasive biomarker ,PSA ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients.
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- 2022
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115. Epigenetic and post‐transcriptional regulation of somatostatin receptor subtype 5 (SST5) in pituitary and pancreatic neuroendocrine tumors
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Sergio Pedraza‐Arevalo, Alejandro Ibáñez‐Costa, Ricardo Blázquez‐Encinas, Miguel R. Branco, Mari C. Vázquez‐Borrego, Aura D. Herrera‐Martínez, Eva Venegas‐Moreno, Raquel Serrano‐Blanch, Álvaro Arjona‐Sánchez, María A. Gálvez‐Moreno, Marta Korbonits, Alfonso Soto‐Moreno, Manuel D. Gahete, Marika Charalambous, Raúl M. Luque, and Justo P. Castaño
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epigenetics ,natural antisense transcript ,neuroendocrine tumors ,pancreas ,pituitary ,SST5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Somatostatin receptor subtype 5 (SST5) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5‐AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5‐AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5‐AS1 expression was assessed by quantitative real‐time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5‐AS1 genes. Results revealed that SSTR5 and SSTR5‐AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5‐AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5‐AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
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- 2022
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116. SF3B1 inhibition disrupts malignancy and prolongs survival in glioblastoma patients through BCL2L1 splicing and mTOR/ß-catenin pathways imbalances
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Antonio C. Fuentes-Fayos, Jesús M. Pérez-Gómez, Miguel E. G-García, Juan M. Jiménez-Vacas, Cristóbal Blanco-Acevedo, Rafael Sánchez-Sánchez, Juan Solivera, Joshua J. Breunig, Manuel D. Gahete, Justo P. Castaño, and Raúl M. Luque
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Glioblastoma ,Splicing factor SF3B1 ,Glioma mouse models ,Antitumor therapy ,BCL2L1 splicing variants ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Glioblastoma is one of the most devastating cancer worldwide based on its locally aggressive behavior and because it cannot be cured by current therapies. Defects in alternative splicing process are frequent in cancer. Recently, we demonstrated that dysregulation of the spliceosome is directly associated with glioma development, progression, and aggressiveness. Methods Different human cohorts and a dataset from different glioma mouse models were analyzed to determine the mutation frequency as well as the gene and protein expression levels between tumor and control samples of the splicing-factor-3B-subunit-1 (SF3B1), an essential and druggable spliceosome component. SF3B1 expression was also explored at the single-cell level across all cell subpopulations and transcriptomic programs. The association of SF3B1 expression with relevant clinical data (e.g., overall survival) in different human cohorts was also analyzed. Different functional (proliferation/migration/tumorspheres and colonies formation/VEGF secretion/apoptosis) and mechanistic (gene expression/signaling pathways) assays were performed in three different glioblastomas cell models (human primary cultures and cell lines) in response to SF3B1 blockade (using pladienolide B treatment). Moreover, tumor progression and formation were monitored in response to SF3B1 blockade in two preclinical xenograft glioblastoma mouse models. Results Our data provide novel evidence demonstrating that the splicing-factor-3B-subunit-1 (SF3B1, an essential and druggable spliceosome component) is low-frequency mutated in human gliomas (~ 1 %) but widely overexpressed in glioblastoma compared with control samples from the different human cohorts and mouse models included in the present study, wherein SF3B1 levels are associated with key molecular and clinical features (e.g., overall survival, poor prognosis and/or drug resistance). Remarkably, in vitro and in vivo blockade of SF3B1 activity with pladienolide B drastically altered multiple glioblastoma pathophysiological processes (i.e., reduction in proliferation, migration, tumorspheres formation, VEGF secretion, tumor initiation and increased apoptosis) likely by suppressing AKT/mTOR/ß-catenin pathways, and an imbalance of BCL2L1 splicing. Conclusions Together, we highlight SF3B1 as a potential diagnostic and prognostic biomarker and an efficient pharmacological target in glioblastoma, offering a clinically relevant opportunity worth to be explored in humans.
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- 2022
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117. Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier
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Pablo Vargas-Rodríguez, Alejandro Cuenca-Martagón, Julia Castillo-González, Ignacio Serrano-Martínez, Raúl M. Luque, Mario Delgado, and Elena González-Rey
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blood-brain barrier ,mesenchymal stem cell ,neurodegenerative diseases ,Alzheimer’s disease ,neuroinflammation ,Parkinson’s disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer’s disease, Parkinson’s disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts.
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- 2023
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118. The truncated somatostatin receptor sst5TMD4 stimulates the production of pro-angiogenic factors in in vitro and in vivo breast cancer models
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Mario Durán-Prado, Michael D. Culler, Marta Hergueta-Redondo, Raul M Luque, David Rincón-Fernández, Justo P. Castaño, Manuel D. Gahete, and Gema Moreno-Bueno
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medicine.medical_specialty ,Breast cancer ,Endocrinology ,Somatostatin receptor ,In vivo ,Internal medicine ,medicine ,Cancer research ,Somatostatin receptor 2 ,Somatostatin receptor 1 ,Biology ,medicine.disease ,In vitro - Published
- 2014
119. Evidence for truncated somatostatin receptor 5 modulation of therapy response to somatostatin analogues in two patients with acromegaly and severe headache
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Ulla Feldt-Rasmussen, Pia Burman, Olivera Casar-Borota, Justo P. Castaño, Marianne Klose, Djordje Marina, and Raul M Luque
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Severe headache ,medicine.medical_specialty ,education.field_of_study ,Somatostatin receptor-5 ,business.industry ,medicine.disease ,Somatostatin ,Therapy response ,Endocrinology ,Internal medicine ,Acromegaly ,Medicine ,business ,education - Published
- 2014
120. Engrailed-2 as a novel biomarker for prostate cancer
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Julia Carrasco-Valiente, J.P. Campos-Hernández, Rosa J. Valero, Gomez E. Gomez, María del Carmen Moreno-Manzanaro Moreno, Raul M Luque, Daniel Hormaechea-Agulla, M.J. Requena-Tapia, Justo P. Castaño, S. Pedraza-Arévalo, Manuel D. Gahete, and Alejandro Ibáñez-Costa
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PCA3 ,Prostate cancer ,business.industry ,Urology ,Cancer research ,medicine ,Biomarker (medicine) ,medicine.disease ,business ,engrailed - Published
- 2016
121. Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
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Emilia Alors-Perez, Ricardo Blázquez-Encinas, Sonia Alcalá, Cristina Viyuela-García, Sergio Pedraza-Arevalo, Vicente Herrero-Aguayo, Juan M. Jiménez-Vacas, Andrea Mafficini, Marina E. Sánchez-Frías, María T. Cano, Fernando Abollo-Jiménez, Juan A. Marín-Sanz, Pablo Cabezas-Sainz, Rita T. Lawlor, Claudio Luchini, Laura Sánchez, Juan M. Sánchez-Hidalgo, Sebastián Ventura, Laura Martin-Hijano, Manuel D. Gahete, Aldo Scarpa, Álvaro Arjona-Sánchez, Alejandro Ibáñez-Costa, Bruno Sainz, Raúl M. Luque, and Justo P. Castaño
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Pancreatic cancer ,Splicing-spliceosome ,SF3B1 ,Pladienolide-B ,cancer stem cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel cancer hallmark and an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibited by Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC and interrogated its potential as an actionable target. Methods SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examining associations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derived CSCs served to test Pladienolide-B treatment effects in vitro, and in vivo in zebrafish and mice. Results SF3B1 was overexpressed in human PDAC and associated with tumor grade and lymph-node involvement. SF3B1 levels closely associated with distinct splicing event profiles and expression of key PDAC players (KRAS, TP53). In PDAC cells, Pladienolide-B increased apoptosis and decreased multiple tumor-related features, including cell proliferation, migration, and colony/sphere formation, altering AKT and JNK signaling, and favoring proapoptotic splicing variants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducing their stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCs xenograft tumor growth in vivo in zebrafish and in mice. Conclusion SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer.
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- 2021
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122. Spliceosomal profiling identifies EIF4A3 as a novel oncogene in hepatocellular carcinoma acting through the modulation of FGFR4 splicing
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Juan L. López‐Cánovas, Natalia Hermán‐Sánchez, Maria Trinidad Moreno‐Montilla, Mercedes del Rio‐Moreno, Emilia Alors‐Perez, Marina E. Sánchez‐Frias, Víctor Amado, Rubén Ciria, Javier Briceño, Manuel de laMata, Justo P. Castaño, Manuel Rodriguez‐Perálvarez, Raúl M. Luque, and Manuel D. Gahete
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FGF19 ,liver cancer ,preclinical model ,splicing machinery ,Medicine (General) ,R5-920 - Abstract
Abstract Introduction Altered splicing landscape is an emerging cancer hallmark; however, the dysregulation and implication of the cellular machinery controlling this process (spliceosome components and splicing factors) in hepatocellular carcinoma (HCC) is poorly known. This study aimed to comprehensively characterize the spliceosomal profile and explore its role in HCC. Methods Expression levels of 70 selected spliceosome components and splicing factors and clinical implications were evaluated in two retrospective and six in silico HCC cohorts. Functional, molecular and mechanistic studies were implemented in three cell lines (HepG2, Hep3B and SNU‐387) and preclinical Hep3B‐induced xenograft tumours. Results Spliceosomal dysregulations were consistently found in retrospective and in silico cohorts. EIF4A3, RBM3, ESRP2 and SRPK1 were the most dysregulated spliceosome elements in HCC. EIF4A3 expression was associated with decreased survival and greater recurrence. Plasma EIF4A3 levels were significantly elevated in HCC patients. In vitro EIF4A3‐silencing (or pharmacological inhibition) resulted in reduced aggressiveness, and hindered xenograft‐tumours growth in vivo, whereas EIF4A3 overexpression increased tumour aggressiveness. EIF4A3‐silencing altered the expression and splicing of key HCC‐related genes, specially FGFR4. EIF4A3‐silencing blocked the cellular response to the natural ligand of FGFR4, FGF19. Functional consequences of EIF4A3‐silencing were mediated by FGFR4 splicing as the restoration of non‐spliced FGFR4 full‐length version blunted these effects, and FGFR4 inhibition did not exert further effects in EIF4A3‐silenced cells. Conclusions Splicing machinery is strongly dysregulated in HCC, providing a source of new diagnostic, prognostic and therapeutic options in HCC. EIF4A3 is consistently elevated in HCC patients and associated with tumour aggressiveness and mortality, through the modulation of FGFR4 splicing.
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- 2022
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123. The consequences of changing endogenous GH/IGF1 levels on carcinogen-induced mammary gland tumorigenesis are dependent on metabolic status in mice
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Justo P. Castaño, Steven M. Swanson, Raul M Luque, Jose Cordoba-Chacon, Rhonda D Kineman, Francisco Perez-Jiminez, Manuel D. Gahete, DD Lantvit, and Jose Lopez-Miranda
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medicine.anatomical_structure ,Mammary gland ,medicine ,Cancer research ,Endogeny ,Biology ,Carcinogenesis ,medicine.disease_cause ,Carcinogen - Published
- 2013
124. Functional relevance of truncated SST5 receptor variants
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Manuel D. Gahete, Raul M Luque, Justo P. Castaño, and Alejandro Ibáñez-Costa
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Relevance (information retrieval) ,Computational biology ,Biology ,Receptor - Published
- 2013
125. Energy status and GH/IGF1 axis
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Raul M Luque, Helen C. Christian, Jose Cordoba-Chacon, Rhonda D Kineman, and Manuel D. Gahete
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Physics ,Atomic physics ,Energy (signal processing) - Published
- 2013
126. Measurement of Free Cytosolic Calcium Concentration ([Ca2+]i) in Single CHO-K1 Cells
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Raul M Luque, Justo P. Castaño, and Manuel D. Gahete
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Chemistry ,Strategy and Management ,Mechanical Engineering ,Metals and Alloys ,Biophysics ,Industrial and Manufacturing Engineering ,Cytosolic calcium - Published
- 2012
127. GPCRs Interaction Measurement by Fluorescence Resonance Energy Transfer (FRET)
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Justo P. Castaño, Raul M Luque, and Manuel D. Gahete
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Chemistry ,Strategy and Management ,Mechanical Engineering ,fungi ,Metals and Alloys ,Acceptor ,Industrial and Manufacturing Engineering ,Crystallography ,Förster resonance energy transfer ,Excited state ,Microscopy ,Biophysics ,Molecule ,Fluorescent protein ,Excitation ,G protein-coupled receptor - Abstract
(Abstract) This is a protocol to determine the physical interaction of a G-protein coupled receptor (GPCR) with itself (homodimerization) or with other GPCR (heterodimerazation) using fluorescence resonance energy transfer (FRET). FRET is a distance-dependent interaction between the electronic excited states of two dye molecules (in this case, CFP and YFP) in which excitation is transferred from a donor molecule (CFP) to an acceptor (YFP) molecule without emission of a photon that can be used to determine interaction among YFP- and CFP-tagged GPCRs. Nowadays, FRET microscopy technique can be used to determine interaction between any proteins that retain biological function when expressed as a fusion to the fluorescent protein.
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- 2012
128. A Novel Human Ghrelin Variant Containing Intron 2 (In2-Ghrelin) Is Present in Normal and Tumoral Pituitaries: Potential Pathological Relevance
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Raul M Luque, Manuel D Gahete, Jose Cordoba-Chacon, Laura Lopez-Sanchez, Luis Jimenez-Reina, Miguel A Japon, Pedro Benito, Alfonso Leal-Cerro, Michael D Culler, Rhonda D Kineman, and Justo P Castano
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- 2011
129. Cortistatin Is Not a Somatostatin Analog but Stimulates Prolactin Release and Its Deficit Causes Plasma Insulin Decrease and Male-Selective Glucose Impairment: Role of Ghrelin
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Jose Cordoba-Chacon, Manuel D Gahete, Anabel I Pozo-Salas, Antonio J Martinez-Fuentes, Francisco Gracia-Navarro, Luis De Lecea, Rhonda D Kineman, Justo P Castano, and Raul M Luque
- Published
- 2011
130. Elevated Endogenous GH/IGF-I, Due to Somatotrope-Specific Loss of Both IGF-I and Insulin Receptors, Improves Glucose Clearance, Despite Insulin Resistance
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Manuel D Gahete, Jose Cordoba-Chacon, Chike V Anadumaka, Qing Lin, C Ronald Kahn, Jens C Bruning, Raul M Luque, and Rhonda D Kineman
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- 2011
131. Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes?
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Raul M, Luque, Manuel D, Gahete, Jose, Cordoba-Chacon, Gwen V, Childs, and Rhonda D, Kineman
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Growth Hormone ,Pituitary Gland ,Animals ,Humans ,Article - Abstract
Circulating growth hormone (GH) levels rise in response to nutrient deprivation and fall in states of nutrient excess. Because GH regulates carbohydrate, lipid, and protein metabolism, defining the mechanisms by which changes in metabolism alter GH secretion will aid in our understanding of the cause, progression, and treatment of metabolic diseases. This review will summarize what is currently known regarding the impact of systemic metabolic signals on GH-axis function. In addition, ongoing studies using the Cre/loxP system to generate mouse models with selective somatotrope resistance to metabolic signals will be discussed, where these models will serve to enhance our understanding of the specific role the somatotrope plays in sensing the metabolic environment and adjusting GH output in metabolic extremes.
- Published
- 2011
132. Truncated somatostatin receptors as new players in somatostatin-cortistatin pathophysiology
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José, Córdoba-Chacón, Manuel D, Gahete, Mario, Durán-Prado, Raul M, Luque, and Justo P, Castaño
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RNA Splicing ,Neuropeptides ,Animals ,Humans ,Receptors, Somatostatin ,Somatostatin - Abstract
Somatostatin (SST) and cortistatin (CORT) act through a family of seven transmembrane domain (TMD) receptors (sst1-5) to govern multiple functions, from growth hormone (GH) secretion to neurotransmission, metabolic homeostasis, gastrointestinal and immune function, and tumor cell growth. Thus, SST analogs are used to treat endocrine/tumoral pathologies. Yet, some SST/CORT actions cannot be explained by their interaction with known ssts. We recently identified novel sst5 variants in human, pig, mouse, and rat that lack one or more TMDs and display unique molecular/functional features: they exhibit distinct tissue distribution, divergent responses to SST/CORT, and intracellular localization as opposed to the typical plasma-membrane distribution of full-length ssts. When coexpressed in the same cell, truncated sst5 variants colocalize and physically interact with full-length ssts, providing a molecular basis to disrupt normal sst2/sst5 functioning. This may explain the inverse correlation between hsst5TMD4 expression in pituitary tumors and octreotide responsiveness in acromegaly. Discovery of these new truncated sst5 variants provides novel insights on SST/CORT/sst pathophysiology and suggests new research avenues for the therapeutic potential of this system.
- Published
- 2011
133. Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients
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Jesús Avila, Rhonda D. Kineman, Raul M Luque, Jose Cordoba-Chacon, Justo P. Castaño, Manuel D. Gahete, Francisco Gracia-Navarro, and Alicia Rubio
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Male ,medicine.medical_specialty ,Energy homeostasis ,chemistry.chemical_compound ,Alzheimer Disease ,Internal medicine ,medicine ,Dementia ,Humans ,Receptors, Neurotensin ,Receptor ,Receptors, Ghrelin ,Cognitive deficit ,Neurotensin ,G protein-coupled receptor ,Aged ,Aged, 80 and over ,General Neuroscience ,digestive, oral, and skin physiology ,General Medicine ,medicine.disease ,Ghrelin ,Temporal Lobe ,Psychiatry and Mental health ,Clinical Psychology ,Endocrinology ,chemistry ,nervous system ,Gene Expression Regulation ,Female ,Geriatrics and Gerontology ,medicine.symptom ,Psychology ,Cognition Disorders ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer's disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS-R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology.
- Published
- 2010
134. Impact of gsp oncogene on the mRNA content for somatostatin and dopamine receptors in human somatotropinomas
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Giselle Fernandes, Taboada, Leonardo Vieira, Neto, Raul M, Luque, Jose, Córdoba-Chacón, Evelyn, de Oliveira Machado, Denise Pires, de Carvalho, Rhonda D, Kineman, and Mônica Roberto, Gadelha
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Adenoma ,Adult ,Male ,Adolescent ,Colforsin ,Cell Culture Techniques ,Middle Aged ,Octreotide ,Papio anubis ,Biomarkers, Pharmacological ,Receptors, Dopamine ,Gene Expression Regulation, Neoplastic ,Delayed-Action Preparations ,Pituitary Gland ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Animals ,Humans ,Female ,Pituitary Neoplasms ,Receptors, Somatostatin - Abstract
It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas.To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels.Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin.The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures.Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.
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- 2010
135. Somatostatin and its receptors from fish to mammals
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Manuel D, Gahete, Jose, Cordoba-Chacón, Mario, Duran-Prado, María M, Malagón, Antonio J, Martinez-Fuentes, Francisco, Gracia-Navarro, Raul M, Luque, and Justo P, Castaño
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Mammals ,Fishes ,Animals ,Receptors, Somatostatin ,Somatostatin ,Biological Evolution - Abstract
Somatostatin (SST) and its receptors (sst) make up a molecular family with unique functional complexity and versatility. Widespread distribution and frequent coexpression of sst subtypes underlies the multiplicity of (patho)physiological processes controlled by SST (central nervous system functions, endocrine and exocrine secretion, cell proliferation). This complexity is clearly reflected in the intricate evolutionary development of this molecular family. Recent studies postulate the existence of an ancestral somatostatin/urotensin II (SST/UII) gene, which originated two ancestral, SST and UII, genes by local duplication. Subsequently, segment duplication would have originated two diverging SST genes in both fish (SS1/SS2) and tetrapods [(SST/cortistatin(CST))]. SST/CST actions are mediated by a family of GPCRs (sst1-5) encoded by five different genes. sst1-4 sequences are highly conserved compared with sst5, suggesting unique evolutionary and functional relevance for the latter. Indeed, we recently identified novel truncated but functional sst5 variants in several species, which may help to explain part of the complexity of the SST/CST/sst family. Comparative and phylogenetic analysis of this molecular family would enhance our understanding of its paradigmatic evolutionary complexity and functional versatility.
- Published
- 2010
136. Calcitriol-Mediated Hypercalcemia, Somatostatin Receptors Expression and 25-Hydroxyvitamin D3-1α- Hydroxylase in GIST Tumors
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Yiraldine Herrera-Martínez, María José Contreras González, Sergio Pedraza-Arévalo, Maria del Carmen Guerrero Martínez, Ángela Rodrigo Martínez, Alberto González Menchen, Maria Angeles Blanco Molina, Maria Angeles Gálvez-Moreno, Alberto L. Moreno-Vega, Raúl M. Luque, and Aura D. Herrera-Martínez
- Subjects
hypercalcemia ,calcitriol ,GIST tumor ,somatostatin receptors ,corticoids ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Hypercalcemia is a common complication in cancer patients Mainly caused by Parathyroid hormone-related protein (PTHrP) secretion and metastasis. Calcitriol secretion is a rare source of hypercalcemia in solid tumors, especially in gastrointestinal stromal tumors (GIST). We present a case report of a female patient with a 23 cm gastric GIST that expressed somatostatin-receptors and presented with severe hypercalcemia due to calcitriol secretion. Calcium control was achieved with medical treatment before the use of targeted-directed therapies. Surgery was performed and allowed complete tumor resection. Two years later, patient remains free of disease. Molecular analysis revealed the mRNA expression of 25-hydroxyvitamin D3-1-hydroxylase (1αOHase) and vitamin-D receptors in the tumor cells, confirming the calcitriol-mediated mechanism. Furthermore, the expression of the endotoxin recognition factors CD14 and TLR4 suggests an inflammatory mediated mechanism. Finally, the expression of somatostatin-receptors, especially SST2 might have been related with clinical evolution and prognosis in this patient.
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- 2022
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137. Gold Nanosystems Covered with Doxorubicin/DNA Complexes: A Therapeutic Target for Prostate and Liver Cancer
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Rosa M. Giráldez-Pérez, Elia Grueso, Antonio J. Montero-Hidalgo, Raúl M. Luque, José M. Carnerero, Edyta Kuliszewska, and Rafael Prado-Gotor
- Subjects
chemotherapy ,gold nanoparticles ,DNA compaction ,gemini surfactants ,doxorubicin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA–Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA–Doxo nanotransporters, the conditions for the DNA–Doxo compaction process induced by gold nanoparticles were first explored using fluorescence spectroscopy, circular dichroism and atomic force microscopy techniques. The reverse process, which is fundamental for Doxo liberation at the site of action, was found to occur at higher CAu@16-Ph-16 concentrations using these techniques. Zeta potential, dynamic light scattering and UV–visible spectroscopy reveal that the prepared compacted nanosystems are stable, highly charged and of adequate size for the effective delivery of Doxo to the cell. This fact is verified by in vitro biocompatibility and internalization studies using two prostate cancer-derived cell lines (LNCaP and DU145) and one hepatocellular carcinoma-derived cell line (SNU-387), as well as a non-tumor prostate (PNT2) cell line and a non-hepatocarcinoma hepatoblastoma cell line (Hep-G2) model used as a control in liver cells. However, the most outstanding results of this work are derived from the use of the CI+NI combined treatments which present strong action in cancer-derived cell lines, while a protective effect is observed in non-tumor cell lines. Hence, novel therapeutic targets based on gold nanoparticles denote high selectivity compared to conventional treatment based on free Doxo at the same concentration. The results obtained show the viability of both the proposed methodology for internalization of compacted nanocomplexes inside the cell and the effectiveness of the possible treatment and minimization of side effects in prostate and liver cancer.
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- 2022
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138. Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin
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Prudencio Sáez-Martínez, Francisco Porcel-Pastrana, Jesús M. Pérez-Gómez, Sergio Pedraza-Arévalo, Enrique Gómez-Gómez, Juan M. Jiménez-Vacas, Manuel D. Gahete, and Raúl M. Luque
- Subjects
somatostatin ,cortistatin ,prostate cancer ,somatostatin analogues ,therapeutic tool ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.
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- 2022
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139. Editorial: Pathophysiological Interrelationship Between Obesity, Metabolic Diseases, and Cancer
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Manuel D. Gahete, Riccarda Granata, and Raúl M. Luque
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obesity ,cancer ,metabolic syndrome ,tumor ,metabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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140. A novel human tumoroid 3D model of sustained ACTH-secreting cell cultures to study critically needed therapies for Cushing's disease
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Antonio C. Fuentes-Fayos and Raúl M. Luque
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Medicine ,Medicine (General) ,R5-920 - Published
- 2021
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141. Morphofunctional and Molecular Assessment of Nutritional Status in Head and Neck Cancer Patients Undergoing Systemic Treatment: Role of Inflammasome in Clinical Nutrition
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Soraya León-Idougourram, Jesús M. Pérez-Gómez, Concepción Muñoz Jiménez, Fernando L-López, Gregorio Manzano García, María José Molina Puertas, Natalia Herman-Sánchez, Rosario Alonso-Echague, Alfonso Calañas Continente, María Ángeles Gálvez Moreno, Raúl M. Luque, Manuel D. Gahete, and Aura D. Herrera-Martínez
- Subjects
head and neck cancer ,malnutrition ,sarcopenia ,comorbidities ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Malnutrition in patients with head and neck cancer is frequent, multifactorial and widely associated with clinical evolution and prognosis. Accurate nutritional assessments allow for early identification of patients at risk of malnutrition in order to start nutritional support and prevent sarcopenia. We aimed to perform a novel morphofunctional nutritional evaluation and explore changes in inflammasome-machinery components in 45 patients with head and neck cancer who are undergoing systemic treatment. To this aim, an epidemiological/clinical/anthropometric/biochemical evaluation was performed. Serum RCP, IL6 and molecular expression of inflammasome-components and inflammatory-associated factors (NOD-like-receptors, inflammasome-activation-components, cytokines and inflammation/apoptosis-related components, cell-cycle and DNA-damage regulators) were evaluated in peripheral-blood mononuclear-cells (PBMCs). Clinical-molecular correlations/associations were analyzed. Coherent and complementary information was obtained in the morphofunctional nutritional assessment of the patients when bioimpedance, anthropometric and ultrasound data were analyzed. These factors were also correlated with different biochemical and molecular parameters, revealing the complementary aspect of the whole evaluation. Serum reactive C protein (RCP) and IL6 were the most reliable parameters for determining patients with decreased standardized phase angle, which is associated with increased mortality in patients with solid malignancies. Several inflammasome-components were dysregulated in patients with malnutrition, decreased phase angle and dependency grade or increased circulating inflammation markers. A molecular fingerprint based on gene-expression of certain inflammasome factors (p27/CCL2/ASC) in PBMCs accurately differentiated patients with and without malnutrition. In conclusion, malnutrition induces a profound alteration in the gene-expression pattern of inflammasome-machinery components in PBMCs. A comprehensive nutritional assessment including novel morphofunctional techniques and molecular markers allows a broad characterization of the nutritional status in cancer patients. Profile of certain inflammasome-components should be further studied as potential targets for nutrition-focused treatment strategies in cancer patients.
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- 2022
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142. Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features, and Somatostatin Analogs Resistance
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Antonio C. Fuentes-Fayos, Miguel E. G-García, Jesús M. Pérez-Gómez, Annabel Peel, Cristóbal Blanco-Acevedo, Juan Solivera, Alejandro Ibáñez-Costa, Manuel D. Gahete, Justo P. Castaño, and Raúl M. Luque
- Subjects
sst5TMD4 ,somatostatin receptor ,splicing variant ,glioblastoma ,somatostatin analogs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.
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- 2022
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143. Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
- Author
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Juan M. Jiménez-Vacas, Vicente Herrero-Aguayo, Antonio J. Montero-Hidalgo, Enrique Gómez-Gómez, Antonio C. Fuentes-Fayos, Antonio J. León-González, Prudencio Sáez-Martínez, Emilia Alors-Pérez, Sergio Pedraza-Arévalo, Teresa González-Serrano, Oscar Reyes, Ana Martínez-López, Rafael Sánchez-Sánchez, Sebastián Ventura, Elena M. Yubero-Serrano, María J. Requena-Tapia, Justo P. Castaño, Manuel D. Gahete, and Raúl M. Luque
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC. Keywords: Prostate cancer, Splicing, Spliceosome, SNRNP200, SRSF3, SRRM1, Therapeutic target
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- 2020
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144. The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions
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Mari C. Vázquez-Borrego, Antonio C. Fuentes-Fayos, Manuel D. Gahete, Justo P. Castaño, Rhonda D. Kineman, and Raúl M. Luque
- Subjects
Pituitary ,Metformin ,Phenformin ,Growth hormone ,Primates ,Hormones ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Biguanides are anti-hyperglycaemic agents used to treat diabetes by acting primarily on the liver, inhibiting hepatic gluconeogenesis. However, biguanides may target other key metabolic tissues to exert beneficial actions. As the “master endocrine gland”, the pituitary is a true homeostatic sensor that controls whole body homeostasis and metabolism by integrating central and peripheral signals. However, whether the pituitary is a primary site of biguanides action in normal adult humans/primates remains unknown. Therefore, we aimed to elucidate the direct effects of two biguanides (metformin/phenformin) on the expression and secretion of all anterior pituitary hormones in two non-human primate species (Papio anubis and Macaca fascicularis), and the molecular/signalling-mechanisms behind these actions. Methods: Primary pituitary cell cultures from baboons and macaques were used to determine the direct impact of metformin/phenformin (alone and combined with primary regulators) on the functioning of all pituitary cell-types (i.e. expression/secretion/signaling-pathways, etc). Results: Metformin/phenformin inhibited basal, but not GHRH/ghrelin-stimulated GH/ACTH/ FSH-secretion and GH/POMC-expression, without altering secretion or expression of other pituitary hormones (PRL/LH/TSH), FSH-expression or cell viability in both primate models. These biguanide actions are likely mediated through modulation of: 1) common (mTOR/PI3K/intracellular-Ca2+mobilization) and distinct (MAPK) signaling pathways; and 2) gene expression of key receptors regulating somatotrope/corticotrope/gonadotrope function (i.e. upregulation of SSTR2/SSTR5/INSR/IGF1R/LEPR). Conclusion: The pituitary gland is a primary target of biguanide actions wherein they modulate somatotrope/corticotrope/gonadotrope-function through multiple molecular/signaling pathways in non-human primate-models. This suggests that the well-known metabolic effects of biguanides might be, at least in part, influenced by their actions at the pituitary level.
- Published
- 2018
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145. Sarcopenia and Ghrelin System in the Clinical Outcome and Prognosis of Gastroenteropancreatic Neuroendocrine Neoplasms
- Author
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Yiraldine Herrera-Martínez, Carlos Alzas Teomiro, Soraya León Idougourram, María José Molina Puertas, Alfonso Calañas Continente, Raquel Serrano Blanch, Justo P. Castaño, María Ángeles Gálvez Moreno, Manuel D. Gahete, Raúl M. Luque, and Aura D. Herrera-Martínez
- Subjects
NENs ,sarcopenia ,CT scan ,ghrelin system ,nutrition ,outcome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Malnutrition and sarcopenia affect clinical outcomes and treatment response in cancer patients. Patients with neuroendocrine neoplasms (NENs) may present with additional symptoms related to tumor localization in the gastrointestinal tract and hormone secretion, increasing the risk and effects of sarcopenia. Aim: To explore the presence of malnutrition and sarcopenia in gastroenteropancreatic (GEP)-NEN patients, their relation to tumor characteristics, patient outcomes, survival and the molecular expression of ghrelin system components in the tumor. Patients and methods: One-hundred-and-four patients were included. Anthropometric, biochemical and CT-scans at diagnosis were evaluated. The expression levels of key ghrelin system components were assessed in 63 tumor samples. Results: Nutritional parameters were similar in GEP-NEN tumors of different origin. Relapsed disease was associated with decreased BMI. Patients who presented with weight loss at diagnosis had significantly lower overall survival (108 (25–302) vs. 263 (79–136) months). Ghrelin O-acyltransferase (GOAT) enzyme expression was higher in these patients. The prevalence of sarcopenia using CT images reached 87.2%. Mortality was observed only in patients with sarcopenia. Muscle evaluation was correlated with biochemical parameters but not with the expression of ghrelin system components. Conclusion: Survival is related to the nutritional status of patients with GEP-NENs and also to the molecular expression of some relevant ghrelin system components. Routine nutritional evaluation should be performed in these patients, in order to prescribe appropriate nutritional support, when necessary, for increasing quality of life and improving clinical outcomes.
- Published
- 2021
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146. Molecular and Clinical Implications of Somatostatin Receptor Profile and Somatostatin Analogues Treatment in Oral Cavity Squamous Cell Carcinoma
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Alba Sanjuan-Sanjuan, Emilia Alors-Perez, Marina Sanchez-Frías, Alicia Dean-Ferrer, Manuel D. Gahete, Susana Heredero-Jung, and Raúl M. Luque
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somatostatin receptors ,oral cavity cancer ,head and neck ,biomarkers ,somatostatin analogues ,therapeutic tool ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Oral squamous cell carcinoma (OSCC) incidence has increased by 50% over the last decade. Unfortunately, surgery and adjuvant radiotherapy and chemotherapy are still the mainstream modality of treatment, underscoring the need for alternative therapies. Somatostatin-analogues (SSA) are efficacious and safe treatments for a variety of tumors, but the presence of somatostatin-receptors (SSTs) and pharmacological effects of SSA on OSCC are poorly known. In this study, we demonstrated that SST2 and SST3 levels were significantly higher in OSCC, compared to adjacent healthy control tissues. SST2 expression was associated with less regional metastasis and a lower recurrence rate. Moreover, SST2 was elevated in OSCC and associated with histopathological good prognosis factors, such as high peritumoral inflammation, smaller depth of invasion, and expansive vs. infiltrative front of tumor invasion. Importantly, treatment with different SSA (octreotide, lanreotide, and pasireotide) significantly reduced cell-proliferation in OSCC primary cell cultures. Altogether, this study demonstrated that SST2 is overexpressed in OSCC vs. healthy tissues and could represent a novel prognostic biomarker, since its expression is associated with tumors that show better prognostic factors and less recurrent rate. Moreover, our data unveil clear antitumoral effects of SSAs on OSCC, opening new avenues to explore their potential as targeting therapy to OSCC.
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- 2021
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147. Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling
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Iacopo Gesmundo, Giuseppina Granato, Antonio C. Fuentes-Fayos, Clara V. Alvarez, Carlos Dieguez, Maria Chiara Zatelli, Noemi Congiusta, Dana Banfi, Nunzia Prencipe, Sheila Leone, Luigi Brunetti, Justo P. Castaño, Raúl M. Luque, Renzhi Cai, Wei Sha, Ezio Ghigo, Andrew V. Schally, and Riccarda Granata
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GHRH ,GH-secreting pituitary adenoma ,ACTH-secreting pituitary adenomas ,cell viability ,apoptosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs.
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- 2021
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148. Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells
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Antonio J. León-González, Prudencio Sáez-Martínez, Juan M. Jiménez-Vacas, Vicente Herrero-Aguayo, Antonio J. Montero-Hidalgo, Enrique Gómez-Gómez, Andrés Madrona, Justo P. Castaño, José L. Espartero, Manuel D. Gahete, and Raúl M. Luque
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anticancer ,extra virgin olive oil ,hydroxytyrosol ,prostate cancer ,semisynthetic derivatives ,Therapeutics. Pharmacology ,RM1-950 - Abstract
A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.
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- 2021
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149. The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness
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Daniel Hormaechea-Agulla, Manuel D. Gahete, Juan M. Jiménez-Vacas, Enrique Gómez-Gómez, Alejandro Ibáñez-Costa, Fernando L-López, Esther Rivero-Cortés, André Sarmento-Cabral, José Valero-Rosa, Julia Carrasco-Valiente, Rafael Sánchez-Sánchez, Rosa Ortega-Salas, María M. Moreno, Natia Tsomaia, Steve M. Swanson, Michael D. Culler, María J. Requena, Justo P. Castaño, and Raúl M. Luque
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Ghrelin-system ,In1-ghrelin variant ,Prostate cancer ,Aggressiveness ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). Methods In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). Results In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. Conclusions Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.
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- 2017
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150. Dietary Intervention Modulates the Expression of Splicing Machinery in Cardiovascular Patients at High Risk of Type 2 Diabetes Development: From the CORDIOPREV Study
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Mercedes del Río-Moreno, Raúl M. Luque, Oriol A. Rangel-Zúñiga, Emilia Alors-Pérez, Juan F. Alcalá-Diaz, Irene Roncero-Ramos, Antonio Camargo, Manuel D. Gahete, José López-Miranda, and Justo P. Castaño
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Low-Fat diet ,Mediterranean diet ,peripheral blood mononuclear cells (PBMCs) ,splicing machinery ,Type-2 diabetes mellitus ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Type-2 diabetes mellitus (T2DM) has become a major health problem worldwide. T2DM risk can be reduced with healthy dietary interventions, but the precise molecular underpinnings behind this association are still incompletely understood. We recently discovered that the expression profile of the splicing machinery is associated with the risk of T2DM development. Thus, the aim of this work was to evaluate the influence of 3-year dietary intervention in the expression pattern of the splicing machinery components in peripheral blood mononuclear cells (PBMCs) from patients within the CORDIOPREV study. Expression of splicing machinery components was determined in PBMCs, at baseline and after 3 years of follow-up, from all patients who developed T2DM (Incident-T2DM, n = 107) and 108 randomly selected non-T2DM subjects, who were randomly enrolled in two healthy dietary patterns (Mediterranean or low-fat diets). Dietary intervention modulated the expression of key splicing machinery components (i.e., up-regulation of SPFQ/RMB45/RNU6, etc., down-regulation of RNU2/SRSF6) after three years, independently of the type of healthy diet. Some of these changes (SPFQ/RMB45/SRSF6) were associated with key clinical features and were differentially induced in Incident-T2DM patients and non-T2DM subjects. This study reveals that splicing machinery can be modulated by long-term dietary intervention, and could become a valuable tool to screen the progression of T2DM.
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- 2020
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