70 results on '"Vandier C"'
Search Results
2. Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy
- Author
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Perrouin‐Verbe, M. A., primary, Schoentgen, N., additional, Talagas, M., additional, Garlantezec, R., additional, Uguen, A., additional, Doucet, L., additional, Rosec, S., additional, Marcorelles, P., additional, Potier‐Cartereau, M., additional, Vandier, C., additional, Ferec, C., additional, Fromont, G., additional, Fournier, G., additional, Valeri, A., additional, and Mignen, O., additional
- Published
- 2019
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3. PO-041 TNF pathway in metastatic colorectal cancer according to RAS status and implication of potassium channels
- Author
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Ibrahim, S., primary, Girault, A., additional, Babin, L., additional, Guéguinou, M., additional, Potier-Cartereau, M., additional, Vandier, C., additional, Paintaud, G., additional, Lecomte, T., additional, and Raoul, W., additional
- Published
- 2018
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4. Glyco-phospho-glycero-ether lipid as modulator of SK3 ion channel and SK3-dependent cancer cell migration
- Author
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Sevrain, C. M., primary, Berthe, W., additional, Couthon-Gourvès, H., additional, Haelters, J. P., additional, Bouchet, A. M., additional, Chantôme, A., additional, Potier-Cartereau, M., additional, Vandier, C., additional, and Jaffrès, P. A., additional
- Published
- 2016
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5. P01 scorpion toxin, a potential therapeutic agent against glioblastoma
- Author
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Mlayah-Bellalouna, S., primary, Chantome, A., additional, Aissaoui, D., additional, Ben Aissa, R., additional, Chagour, T., additional, Vandier, C., additional, El Ayeb, M., additional, and Srairi-Abid, N., additional
- Published
- 2016
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- View/download PDF
6. Spontaneous nanotube formation of an asymmetric glycolipid.
- Author
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Villanueva ME, Bar L, Redondo-Morata L, Namdar P, Ruysschaert JM, Pabst G, Vandier C, María Bouchet A, and Losada-Pérez P
- Abstract
Over the past decades, advances in lipid nanotechnology have shown that self-assembled lipid structures providing ease of preparation, chemical stability, and biocompatibility represent a landmark on the development of multidisciplinary technologies. Lipid nanotubes (LNTs) are a unique class of lipid self-assembled structures, bearing unique properties such as high-aspect ratio, tunable diameter size, and precise molecular recognition. They can be obtained either by the action of external factors to already formed vesicles or spontaneously, the latter depending strongly on subtle molecular features. Here, we report on the spontaneous formation of supported lipid nanotubes of a particular type of glycolipid, ohmline, whose hydrophobic core displays remarkable asymmetry. The combination of bulk and surface-sensitive techniques indicates that below its main transition, ohmline displays an interdigitated gel phase, likely driven by the unique asymmetry in its hydrophobic core. Enhanced order packing by interdigitation favors the formation of ohmline nanotubes in agreement with chiral-based models of nanotube formation. The findings presented in this work call for additional studies to link lipid molecular structure-assembly relationships, whose understanding is relevant for the controlled design of lipid nanotubes networks in particular and controlled design of soft-matter nanomaterials in general., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Publisher Correction: LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.
- Author
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Proteau S, Krossa I, Husser C, Guéguinou M, Sella F, Bille K, Irondelle M, Dalmasso M, Barouillet T, Cheli Y, Pisibon C, Arrighi N, Nahon-Estève S, Martel A, Gastaud L, Lassalle S, Mignen O, Brest P, Mazure NM, Bost F, Baillif S, Landreville S, Turcotte S, Hasson D, Carcamo S, Vandier C, Bernstein E, Yvan-Charvet L, Levesque MP, Ballotti R, Bertolotto C, and Strub T
- Published
- 2024
- Full Text
- View/download PDF
8. Endogenous ether lipids differentially promote tumor aggressiveness by regulating the SK3 channel.
- Author
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Papin M, Fontaine D, Goupille C, Figiel S, Domingo I, Pinault M, Guimaraes C, Guyon N, Cartron PF, Emond P, Lefevre A, Gueguinou M, Crottès D, Jaffrès PA, Ouldamer L, Maheo K, Fromont G, Potier-Cartereau M, Bougnoux P, Chantôme A, and Vandier C
- Subjects
- Humans, Cell Movement, MicroRNAs metabolism, MicroRNAs genetics, Lipids chemistry, Cell Line, Tumor, Neoplasm Invasiveness, Neoplasms metabolism, Neoplasms pathology, Neoplasms genetics, Small-Conductance Calcium-Activated Potassium Channels metabolism, Small-Conductance Calcium-Activated Potassium Channels genetics
- Abstract
SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9-dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests with the contents of article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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9. Enhanced macromolecular substance extravasation through the blood-brain barrier via acoustic bubble-cell interactions.
- Author
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Chen J, Escoffre JM, Romito O, Iazourene T, Presset A, Roy M, Potier Cartereau M, Vandier C, Wang Y, Wang G, Huang P, and Bouakaz A
- Subjects
- Brain metabolism, Acoustics, Microbubbles, Coloring Agents, Drug Delivery Systems methods, Cell Communication, Blood-Brain Barrier metabolism, Dextrans
- Abstract
The blood-brain barrier (BBB) maintains brain homeostasis, regulates influx and efflux transport, and provides protection to the brain tissue. Ultrasound (US) and microbubble (MB)-mediated blood-brain barrier opening is an effective and safe technique for drug delivery in-vitro and in-vivo. However, the exact mechanism underlying this technique is still not fully elucidated. The aim of the study is to explore the contribution of transcytosis in the BBB transient opening using an in-vitro model of BBB. Utilizing a diverse set of techniques, including Ca
2+ imaging, electron microscopy, and electrophysiological recordings, our results showed that the combined use of US and MBs triggers membrane deformation within the endothelial cell membrane, a phenomenon primarily observed in the US + MBs group. This deformation facilitates the vesicles transportation of 500 kDa fluorescent Dextran via dynamin-/caveolae-/clathrin- mediated transcytosis pathway. Simultaneously, we observed increase of cytosolic Ca2+ concentration, which is related with increased permeability of the 500 kDa fluorescent Dextran in-vitro. This was found to be associated with the Ca2+ -protein kinase C (PKC) signaling pathway. The insights provided by the acoustically-mediated interaction between the microbubbles and the cells delineate potential mechanisms for macromolecular substance permeability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
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10. LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.
- Author
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Proteau S, Krossa I, Husser C, Guéguinou M, Sella F, Bille K, Irondelle M, Dalmasso M, Barouillet T, Cheli Y, Pisibon C, Arrighi N, Nahon-Estève S, Martel A, Gastaud L, Lassalle S, Mignen O, Brest P, Mazure NM, Bost F, Baillif S, Landreville S, Turcotte S, Hasson D, Carcamo S, Vandier C, Bernstein E, Yvan-Charvet L, Levesque MP, Ballotti R, Bertolotto C, and Strub T
- Subjects
- Humans, Calcium, Cell Proliferation, Reactive Oxygen Species, Melanoma drug therapy, Uveal Neoplasms genetics, Uveal Neoplasms pathology
- Abstract
Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na
+ /Ca2+ ) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. Our study also identified an LKB1-loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2023
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11. Ether-lipids and cellular signaling: A differential role of alkyl- and alkenyl-ether-lipids?
- Author
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Papin M, Bouchet AM, Chantôme A, and Vandier C
- Subjects
- Plasmalogens metabolism, Ether, Ethers chemistry
- Abstract
Ether-lipids (EL) are specific lipids bearing a characteristic sn-1 ether bond. Depending on the ether or vinyl-ether nature of this bond, they are present as alkyl- or alkenyl-EL, respectively. Among EL, alkenyl-EL, also referred as plasmalogens in the literature, attract most of the scientific interest as they are the predominant EL species in eukaryotic cells, thus less is known about alkyl-EL. EL have been implicated in various signaling pathways and alterations in their quantity are frequently observed in pathologies such as neurodegenerative and cardiovascular diseases or cancer. However, it remains unknown whether both alkyl- and alkenyl-EL play the same roles in these processes. This review summarizes the roles and mechanisms of action of EL in cellular signaling and tries to discriminate between alkyl- and alkenyl-EL. We also focus on the involvement of EL-mediated alterations of cellular signaling in diseases and discuss the potential interest for EL in therapy., (Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
- Published
- 2023
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12. Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression.
- Author
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Kouba S, Buscaglia P, Guéguinou M, Ibrahim S, Félix R, Guibon R, Fromont G, Pigat N, Capiod T, Vandier C, Mignen O, and Potier-Cartereau M
- Abstract
Prostate cancer (PCa) represents one of the most frequent diagnosed cancer in males worldwide. Due to routine screening tests and the efficiency of available treatments, PCa-related deaths have significantly decreased over the past decades. However, PCa remains a critical threat if detected at a late stage in which, cancer cells would have already detached from the primary tumor to spread and invade other parts of the body. Calcium (Ca
2+ ) channels and their protein regulators are now considered as hallmarks of cancer and some of them have been well examined in PCa. Among these Ca2+ channels, isoform 3 of the ORAI channel family has been shown to regulate the proliferation of PCa cells via the Arachidonic Acid-mediated Ca2+ entry, requiring the involvement of STIM1 (Stromal Interaction Molecule 1). Still, no study has yet demonstrated a role of the "neglected" STIM2 isoform in PCa or if it may interact with ORAI3 to promote an oncogenic behavior. In this study, we demonstrate that ORAI3 and STIM2 are upregulated in human PCa tissues. In old KIMAP (Knock-In Mouse Prostate Adenocarcinoma) mice, ORAI3 and STIM2 mRNA levels were significantly higher than ORAI1 and STIM1. In vitro, we show that ORAI3-STIM2 interact under basal conditions in PC-3 cells. ORAI3 silencing increased Store Operated Ca2+ Entry (SOCE) and induced a significant increase of the cell population in G2/M phase of the cell cycle, consistent with the role of ORAI3 as a negative regulator of SOCE. Higher expression levels of CDK1-Y15/Cyclin B1 were detected and mitotic arrest-related death occurred after ORAI3 silencing, which resulted in activating Bax/Bcl-2-mediated apoptotic pathway and caspase-8 activation and cleavage. STIM2 and ORAI3 expression increased in M phase while STIM1 expression and SOCE amplitude significantly decreased. Taken together, ORAI3 -STIM2 complex allows a successful progression through mitosis of PCa cells by evading mitotic catastrophe., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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13. SK C a - and Kv1-type potassium channels and cancer: Promising therapeutic targets?
- Author
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Dupuy M, Gueguinou M, Potier-Cartereau M, Lézot F, Papin M, Chantôme A, Rédini F, Vandier C, and Verrecchia F
- Subjects
- Humans, Apoptosis, Ion Channels, Potassium Channels, Shaker Superfamily of Potassium Channels, Neoplasms pathology
- Abstract
Ion channels are transmembrane structures that allow the passage of ions across cell membranes such as the plasma membrane or the membranes of various organelles like the nucleus, endoplasmic reticulum, Golgi apparatus or mitochondria. Aberrant expression of various ion channels has been demonstrated in several tumor cells, leading to the promotion of key functions in tumor development, such as cell proliferation, resistance to apoptosis, angiogenesis, invasion and metastasis. The link between ion channels and these key biological functions that promote tumor development has led to the classification of cancers as oncochannelopathies. Among all ion channels, the most varied and numerous, forming the largest family, are the potassium channels, with over 70 genes encoding them in humans. In this context, this review will provide a non-exhaustive overview of the role of plasma membrane potassium channels in cancer, describing 1) the nomenclature and structure of potassium channels, 2) the role of these channels in the control of biological functions that promotes tumor development such as proliferation, migration and cell death, and 3) the role of two particular classes of potassium channels, the SKCa- and Kv1- type potassium channels in cancer progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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14. Insights into the mechanisms governing P01 scorpion toxin effect against U87 glioblastoma cells oncogenesis.
- Author
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Mlayah-Bellalouna S, Aissaoui-Zid D, Chantome A, Jebali J, Souid S, Ayedi E, Mejdoub H, Belghazi M, Marrakchi N, Essafi-Benkhadir K, Vandier C, and Srairi-Abid N
- Abstract
The emerging concept of small conductance Ca
2+ -activated potassium channels (SKCa ) as pharmacological target for cancer treatment has significantly increased in recent years. In this study, we isolated the P01 toxin from Androctonus australis (Aa) scorpion venom and investigated its effect on biological properties of glioblastoma U87, breast MDA-MB231 and colon adenocarcinoma LS174 cancer cell lines. Our results showed that P01 was active only on U87 glioblastoma cells. It inhibited their proliferation, adhesion and migration with IC50 values in the micromolar range. We have also shown that P01 reduced the amplitude of the currents recorded in HEK293 cells expressing SK2 channels with an IC50 value of 3 pM, while it had no effect on those expressing SK3 channels. The investigation of the SKCa channels expression pattern showed that SK2 transcripts were expressed differently in the three cancer cell lines. Particularly, we highlighted the presence of SK2 isoforms in U87 cells, which could explain and rely on the specific activity of P01 on this cell line. These experimental data highlighted the usefulness of scorpion peptides to decipher the role of SKCa channels in the tumorigenesis process, and develop potential therapeutic molecules targeting glioblastoma with high selectivity., 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 Mlayah-Bellalouna, Aissaoui-Zid, Chantome, Jebali, Souid, Ayedi, Mejdoub, Belghazi, Marrakchi, Essafi-Benkhadir, Vandier and Srairi-Abid.)- Published
- 2023
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15. Orai1/KCa/SigmaR1 complex, the cancer cell suicide squad.
- Author
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Gautier M and Vandier C
- Subjects
- Humans, Calcium metabolism, Cell Line, Tumor, ORAI1 Protein, Stromal Interaction Molecule 1, Neoplasms
- Published
- 2022
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16. The Sodium-Calcium Exchanger Controls the Membrane Potential of AFT024: A Mesenchymal Stem Cell Hematopoietic Niche Forming Line.
- Author
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Potier-Cartereau M, Gautier M, Ravalet N, Ducrocq E, Hamard S, LeGuennec JY, Vandier C, and Herault O
- Abstract
The aim of this study was to characterize the functional expression of sodium-calcium exchangers on AFT024 cell line, a murine model of mesenchymal stem/stromal cells (MSCs) supporting human primitive hematopoiesis. All current-clamp and voltage-clamp experiments were performed using the perforated patch whole-cell recording technique with amphotericin B. The membrane potential of -14 mV shifted to -35 mV when lowering the external sodium concentration to 0.33 mM and an increase of cytosolic calcium concentration was observed. KB-R7943, a selective blocker of cardiac sodium-calcium exchangers, also named NCX1 , induced a hyperpolarization at physiological sodium concentration while it blocked the hyperpolarization observed at low sodium concentration. This demonstrates for the first time the presence of the sodium-calcium exchangers in AFT024 cells and provides initial evidence that the membrane potential of these stromal cells is maintained depolarized by this exchanger. Lowering external sodium concentration and KB-R7943 had no effect on the membrane potential of 2018 cells, a nonhematopoietic-supportive cell line. Since NCX1 is differentially expressed in AFT024 cells as compared with nonhematopoietic supportive cells with more restricted differentiation potential, this study suggests a potential role of this sodium-calcium exchanger, in the differentiation process or hematopoietic support of MSCs., (Copyright 2022, Mary Ann Liebert, Inc., publishers.)
- Published
- 2022
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17. Bioelectricity of the Tumor Microenvironment.
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Buchanan PJ and Vandier C
- Published
- 2022
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18. Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer.
- Author
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Guéguinou M, Ibrahim S, Bourgeais J, Robert A, Pathak T, Zhang X, Crottès D, Dupuy J, Ternant D, Monbet V, Guibon R, Flores-Romero H, Lefèvre A, Lerondel S, Le Pape A, Dumas JF, Frank PG, Girault A, Chautard R, Guéraud F, García-Sáez AJ, Ouaissi M, Emond P, Sire O, Hérault O, Fromont-Hankard G, Vandier C, Tougeron D, Trebak M, Raoul W, and Lecomte T
- Subjects
- Animals, Calcium metabolism, Calcium Signaling, Humans, Mice, Microsatellite Repeats, Mitochondrial Proteins metabolism, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Curcumin pharmacology, Microsatellite Instability, Sodium-Calcium Exchanger antagonists & inhibitors
- Abstract
Background and Aims: Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX., Methods: We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa
2+ ) extrusion, the role of redox metabolism in this process. We evaluated their anti-tumorigenic activity in vitro and in a xenograft mouse model. We analyzed NCLX expression and associations with survival in The Cancer Genome Atlas (TCGA) dataset and in tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC., Results: In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis. NCLX inhibition with pharmacological and molecular approaches reproduced the effects of curcumin. NCLX inhibitors decreased CRC tumor growth in vivo. Both transcriptomic analysis of TCGA dataset and immunohistochemical analysis of tissue microarrays demonstrated that higher NCLX expression was associated with MSI status, and for the first time, NCLX expression was significantly associated with recurrence-free survival., Conclusions: Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2022
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19. CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer.
- Author
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O'Reilly D, Downing T, Kouba S, Potier-Cartereau M, McKenna DJ, Vandier C, and Buchanan PJ
- Subjects
- Androgen Antagonists pharmacology, Androgen Antagonists therapeutic use, Androgens pharmacology, Androgens therapeutic use, Animals, Calcium metabolism, Cell Line, Tumor, Humans, Male, Mice, Up-Regulation, Prostatic Neoplasms drug therapy, Prostatic Neoplasms metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Ca
i 2+ ) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that voltage gated calcium channel (VGCC) expression is increased in cancer, particularly CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai 2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients. This was corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models, which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. Expression was found to be of a shortened 170kDa CaV1.3 isoform associated with plasma and intracellular membranes, which failed to induce calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This mechanism was found to promote the proliferation and survival of ADT resistant CRPC cells. Overall, this study demonstrates for the first time in PCa that under ADT specific CaV1.3 isoforms promote an upregulation of SOCE which contributes to treatment resistance and CRPC biology. Thus, this novel oncochannel represents a target for therapeutic development to improve PCa patient outcomes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
- Full Text
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20. EGFR -Mutant Non-Small-Cell Lung Cancer at Surgical Stages: What Is the Place for Tyrosine Kinase Inhibitors?
- Author
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Cansouline X, Lipan B, Sizaret D, Tallet A, Vandier C, Carmier D, and Legras A
- Abstract
The ADAURA trial has been significant for the perception of EGFR tyrosine kinase inhibitors (TKIs) as a tool for early stage non-small-cell lung cancer (NSCLC). It produced such great insight that the main TKI, Osimertinib, was rapidly integrated into international guidelines for adjuvant use. However, EGFR -mutant NSCLC is a complex entity and has various targeting drugs, and the benefits for patients might not be as clear as they seem. We reviewed trials and meta-analyses considering TKI adjuvant and neoadjuvant use. We also explored the influence of mutation variability and financial evaluations. We found that TKIs often show disease-free survival (DFS) benefits, yet studies have struggled to improve the overall survival (OS); however, the results from the literature might be confusing because of variability in the stages and mutations. The safety profiles and adverse events are acceptable, but costs remain high and accessibility might not be optimal. TKIs are promising drugs that could allow for tailored treatment designs.
- Published
- 2022
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21. Development of a High-Performance Thin-Layer Chromatography Method for the Quantification of Alkyl Glycerolipids and Alkenyl Glycerolipids from Shark and Chimera Oils and Tissues.
- Author
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Papin M, Guimaraes C, Pierre-Aue B, Fontaine D, Pardessus J, Couthon H, Fromont G, Mahéo K, Chantôme A, Vandier C, and Pinault M
- Subjects
- Animals, Chromatography, Thin Layer, Ether, Ethers, Glycerol, Plant Oils, Fish Oils, Sharks, Lipids analysis
- Abstract
Ether lipids are composed of alkyl lipids with an ether bond at the sn-1 position of a glycerol backbone and alkenyl lipids, which possess a vinyl ether bond at the sn-1 position of the glycerol. These ether glycerolipids are present either as polar glycerophospholipids or neutral glycerolipids. Before studying the biological role of molecular species of ether glycerolipids, there is a need to separate and quantify total alkyl and alkenyl glycerolipids from biological samples in order to determine any variation depending on tissue or physiopathological conditions. Here, we detail the development of the first high-performance thin-layer chromatography method for the quantification of total alkyl and alkenyl glycerolipids thanks to the separation of their corresponding alkyl and alkenyl glycerols. This method starts with a reduction of all lipids after extraction, resulting in the reduction of neutral and polar ether glycerolipids into alkyl and alkenyl glycerols, followed by an appropriate purification and, finally, the linearly ascending development of alkyl and alkenyl glycerols on high-performance thin-layer chromatography plates, staining, carbonization and densitometric analysis. Calibration curves were obtained with commercial alkyl and alkenyl glycerol standards, enabling the quantification of alkyl and alkenyl glycerols in samples and thus directly obtaining the quantity of alkyl and alkenyl lipids present in the samples. Interestingly, we found a differential quantity of these lipids in shark liver oil compared to chimera. We quantified alkyl and alkenyl glycerolipids in periprostatic adipose tissues from human prostate cancer and showed the feasibility of this method in other biological matrices (muscle, tumor).
- Published
- 2022
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22. Data pertaining to aberrant intracellular calcium handling during androgen deprivation therapy in prostate cancer.
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O'Reilly D, Downing T, Kouba S, Potier-Cartereau M, McKenna DJ, Vandier C, and Buchanan P
- Abstract
The data generated here in relates to the research article "CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer". A model of prostate cancer (PCa) progression to castration resistance was employed, with untreated androgen sensitive LNCaP cell line alongside two androgen deprived (bicalutamide) sublines, either 10 days (LNCaP-ADT) or 2 years (LNCaP-ABL) treatment, in addition to androgen insensitive PC3. With this PCa model, qPCR was used to examined fold change in markers linked to androgen resistance, androgen receptor ( AR ) and neuron specific enolase ( NSE ), observing an increase under androgen deprivation. In addition, the gene expression of a range of calcium channels was measured, with only the L-type Voltage gated calcium channel, CACNA1D , demonstrating an increase during androgen deprivation. With CACNA1D knockdown the channel was found not to influence the gene expression of calcium channels, ORAI1 and STIM1 . The calcium channel blocker (CCB), nifedipine, was employed to determine the impact of CaV1.3 on the observed store release and calcium entry measured via Fura-2AM ratiometric dye in our outlined PCa model. In both the presence and absence of androgen deprivation, nifedipine was found to have no impact on store release induced by thapsigargin (Tg) in 0mM Ca
2+ nor store operated calcium entry (SOCE) following the addition of 2mM Ca2+ . However, CACNA1D siRNA knockdown was able to reduce SOCE in PC3 cells. The effect of nifedipine on CaV1.3 in PCa biology was measured through cell proliferation assay, with no observed change in the presence of CCB. While siCACNA1D reduced PC3 cell proliferation. This data can be reused to inform new studies investigating altered calcium handling in androgen resistant prostate cancer. It provides insight into the mechanism of CaV1.3 and its functional properties in altered calcium in cancer, which can be of use to researchers investigating this channel in disease. Furthermore, it could be helpful in interpreting studies investigating CCB's as a therapeutic and in the development of future drugs targeting CaV1.3., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)- Published
- 2022
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23. Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide.
- Author
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Moslah W, Aissaoui-Zid D, Aboudou S, Abdelkafi-Koubaa Z, Potier-Cartereau M, Lemettre A, ELBini-Dhouib I, Marrakchi N, Gigmes D, Vandier C, Luis J, Mabrouk K, and Srairi-Abid N
- Subjects
- Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dendrimers chemistry, Dendrimers pharmacology, Humans, Oligopeptides chemistry, Scorpion Venoms chemistry, Scorpions, Antineoplastic Agents pharmacology, Central Nervous System Neoplasms drug therapy, Glioblastoma drug therapy, Oligopeptides pharmacology, Scorpion Venoms pharmacology
- Abstract
Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC
50 value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.- Published
- 2022
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24. Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research.
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Potier-Cartereau M, Raoul W, Weber G, Mahéo K, Rapetti-Mauss R, Gueguinou M, Buscaglia P, Goupille C, Le Goux N, Abdoul-Azize S, Lecomte T, Fromont G, Chantome A, Mignen O, Soriani O, and Vandier C
- Subjects
- Calcium metabolism, Calcium Channels metabolism, Humans, Lipids, Potassium metabolism, Potassium Channels metabolism, Neoplasms drug therapy, Potassium Channels, Voltage-Gated
- Abstract
The intracellular Ca
2+ concentration is mainly controlled by Ca2+ channels. These channels form complexes with K+ channels, which function to amplify Ca2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca2+ channels and non-voltage-gated/voltage-independent Ca2+ channels have been reported to interact with K+ channels such as Ca2+ -activated K+ channels and voltage-gated K+ channels. These channels are activated by an increase in cytosolic Ca2+ concentration or by membrane depolarization, which induces membrane hyperpolarization, increasing the driving force for Ca2+ flux. These complexes, composed of K+ and Ca2+ channels, are regulated by several molecules including lipids (ether lipids and cholesterol), proteins (e.g. STIM), receptors (e.g. S1R/SIGMAR1), and peptides (e.g. LL-37) and can be targeted by monoclonal antibodies, making them novel targets for cancer research., (© 2020. Springer Nature Switzerland AG.)- Published
- 2022
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25. AaTs-1: A Tetrapeptide from Androctonus australis Scorpion Venom, Inhibiting U87 Glioblastoma Cells Proliferation by p53 and FPRL-1 Up-Regulations.
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Aissaoui-Zid D, Saada MC, Moslah W, Potier-Cartereau M, Lemettre A, Othman H, Gaysinski M, Abdelkafi-Koubaa Z, Souid S, Marrakchi N, Vandier C, Essafi-Benkhadir K, and Srairi-Abid N
- Subjects
- Animals, Antineoplastic Agents chemistry, Humans, Oligopeptides chemistry, Scorpions, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioblastoma drug therapy, Glioblastoma metabolism, Oligopeptides pharmacology, Receptors, Formyl Peptide biosynthesis, Receptors, Lipoxin biosynthesis, Scorpion Venoms chemistry, Tumor Suppressor Protein p53 biosynthesis, Up-Regulation drug effects
- Abstract
Glioblastoma is an aggressive cancer, against which medical professionals are still quite helpless, due to its resistance to current treatments. Scorpion toxins have been proposed as a promising alternative for the development of effective targeted glioblastoma therapy and diagnostic. However, the exploitation of the long peptides could present disadvantages. In this work, we identified and synthetized AaTs-1, the first tetrapeptide from Androctonus australis scorpion venom (Aa), which exhibited an antiproliferative effect specifically against human glioblastoma cells. Both the native and synthetic AaTs-1 were endowed with the same inhibiting effect on the proliferation of U87 cells with an IC
50 of 0.56 mM. Interestingly, AaTs-1 was about two times more active than the anti-glioblastoma conventional chemotherapeutic drug, temozolomide (TMZ), and enhanced its efficacy on U87 cells. AaTs-1 showed a significant similarity with the synthetic peptide WKYMVm, an agonist of a G-coupled formyl-peptide receptor, FPRL-1, known to be involved in the proliferation of glioma cells. Interestingly, the tetrapeptide triggered the dephosphorylation of ERK, p38, and JNK kinases. It also enhanced the expression of p53 and FPRL-1, likely leading to the inhibition of the store operated calcium entry. Overall, our work uncovered AaTs-1 as a first natural potential FPRL-1 antagonist, which could be proposed as a promising target to develop new generation of innovative molecules used alone or in combination with TMZ to improve glioblastoma treatment response. Its chemical synthesis in non-limiting quantity represents a valuable advantage to design and develop low-cost active analogues to treat glioblastoma cancer.- Published
- 2021
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26. Synthetic alkyl-ether-lipid promotes TRPV2 channel trafficking trough PI3K/Akt-girdin axis in cancer cells and increases mammary tumour volume.
- Author
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Guéguinou M, Felix R, Marionneau-Lambot S, Oullier T, Penna A, Kouba S, Gambade A, Fourbon Y, Ternant D, Arnoult C, Simon G, Bouchet AM, Chantôme A, Harnois T, Haelters JP, Jaffrès PA, Weber G, Bougnoux P, Carreaux F, Mignen O, Vandier C, and Potier-Cartereau M
- Abstract
The Transient Receptor Potential Vanilloid type 2 (TRPV2) channel is highly selective for Ca
2+ and can be activated by lipids, such as LysoPhosphatidylCholine (LPC). LPC analogues, such as the synthetic alkyl-ether-lipid edelfosine or the endogenous alkyl-ether-lipid Platelet Activating Factor (PAF), modulates ion channels in cancer cells. This opens the way to develop alkyl-ether-lipids for the modulation of TRPV2 in cancer. Here, we investigated the role of 2-Acetamido-2-Deoxy-l-O-Hexadecyl-rac-Glycero-3-PhosphatidylCholine (AD-HGPC), a new alkyl-ether-lipid (LPC analogue), on TRPV2 trafficking and its impact on Ca2+ -dependent cell migration. The effect of AD-HGPC on the TRPV2 channel and tumour process was further investigated using calcium imaging and an in vivo mouse model. Using molecular and pharmacological approaches, we dissected the mechanism implicated in alkyl-ether-lipids sensitive TRPV2 trafficking. We found that TRPV2 promotes constitutive Ca2+ entry, leading to migration of highly metastatic breast cancer cell lines through the PI3K/Akt-Girdin axis. AD-HGPC addresses the functional TRPV2 channel in the plasma membrane through Golgi stimulation and PI3K/Akt/Rac-dependent cytoskeletal reorganization, leading to constitutive Ca2+ entry and breast cancer cell migration (without affecting the development of metastasis), in a mouse model. We describe, for the first time, the biological role of a new alkyl-ether-lipid on TRPV2 channel trafficking in breast cancer cells and highlight the potential modulation of TRPV2 by alkyl-ether-lipids as a novel avenue for research in the treatment of metastatic cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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27. Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation.
- Author
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Bery F, Cancel M, Guéguinou M, Potier-Cartereau M, Vandier C, Chantôme A, Guibon R, Bruyère F, Fromont G, and Mahéo K
- Abstract
Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes.
- Published
- 2021
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28. Thio-ether functionalized glycolipid amphiphilic compounds reveal a potent activator of SK3 channel with vasorelaxation effect.
- Author
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Sevrain CM, Fontaine D, Bauduin A, Guéguinou M, Zhang BL, Chantôme A, Mahéo K, Pasqualin C, Maupoil V, Couthon H, Vandier C, and Jaffrès PA
- Subjects
- Animals, Cell Movement drug effects, Cell Survival drug effects, Cells, Cultured, Ethers chemistry, Glycolipids chemistry, Humans, Male, Rats, Rats, Wistar, Sulfhydryl Compounds chemistry, Surface-Active Agents chemical synthesis, Surface-Active Agents chemistry, Vasodilation drug effects, Ethers pharmacology, Glycolipids pharmacology, Small-Conductance Calcium-Activated Potassium Channels metabolism, Sulfhydryl Compounds pharmacology, Surface-Active Agents pharmacology
- Abstract
The modulation of SK3 ion channels can be efficiently and selectively achieved by using the amphiphilic compound Ohmline (a glyco-glycero-ether-lipid). We report herein a series of Ohmline analogues featuring the replacement of one ether function by a thioether function located at the same position or shifted close to its initial position. The variation of the lipid chain length and the preparation of two analogues featuring either one sulfoxide or one sulfone moiety complete this series. Patch clamp measurements indicate that the presence of the thioether function (compounds 7 and 17a) produces strong activators of SK3 channels, whereas the introduction of a sulfoxide or a sulfone function at the same place produces amphiphiles devoid of an effect on SK3 channels. Compounds 7 and 17a are the first amphiphilic compounds featuring strong activation of SK3 channels (close to 200% activation). The cytosolic calcium concentration determined from fluorescence at 3 different times for compound 7b (13 min, 1 h, 24 h) revealed that the effect is different suggesting that the compound could be metabolized over time. This compound could be used as a strong SK3 activator for a short time. The capacity of 7b to activate SK3 was then used to induce vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. For the first time, we report that an amphiphilic compound can affect the endothelium dependent vasorelaxation.
- Published
- 2021
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29. [NCLX exchanger: An ambivalent role in colorectal cancer timeline].
- Author
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Guéguinou M, Pathak T, Robert A, Vandier C, Trebak M, Lecomte T, and Raoul W
- Subjects
- Adenosine Triphosphate biosynthesis, Calcium metabolism, Calcium Phosphates, Calcium Signaling, Colorectal Neoplasms etiology, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mitochondria metabolism, Mitochondrial Proteins physiology, Reactive Oxygen Species metabolism, Sodium-Calcium Exchanger physiology, Colorectal Neoplasms metabolism, Mitochondrial Proteins metabolism, Sodium-Calcium Exchanger metabolism
- Published
- 2021
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30. Development of pyrene-based fluorescent ether lipid as inhibitor of SK3 ion channels.
- Author
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Bauduin A, Papin M, Chantôme A, Couthon H, Deschamps L, Requejo-Isidro J, Vandier C, and Jaffrès PA
- Subjects
- Cell Line, Tumor, Cell Movement drug effects, Fluorescent Dyes chemistry, Fluorescent Dyes pharmacology, Glycolipids chemistry, HEK293 Cells, Humans, Potassium Channel Blockers chemistry, Pyrenes chemistry, Small-Conductance Calcium-Activated Potassium Channels metabolism, Glycolipids pharmacology, Potassium Channel Blockers pharmacology, Pyrenes pharmacology, Small-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors
- Abstract
We report the synthesis of three bioactive pyrene-based fluorescent analogues of Ohmline which is the most efficient and selective inhibitor of SK3 ion channel. The interaction of these Ohmline-pyrene (OP1-3) with liposomes of different composition reveals that only OP2 and OP3 are readily integrated into liposomes. Fluorescence measurements indicate that, depending on their concentration, OP2 and OP3 exist either as monomer or as a mixture of monomer and excimers within the liposome bilayer. Among the three Ohmline Pyrene compounds (OP1-3) only OP2 is able to reduce SK3 currents and is the first efficient fluorescent modulator of SK3 channel as revealed by patch clamp measurements (- 71.3 ± 13.3% at 10 μM) and by its inhibition of SK3-dependent cancer cell migration at (-32.5% ± 4.8% at 1 μM). We also report the first fluorescence study on living breast cancer cells (MDA-MB-231) showing that OP2 is rapidly integrated in bio-membranes followed by cell internalization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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31. Novel Blocker of Onco SK3 Channels Derived from Scorpion Toxin Tamapin and Active against Migration of Cancer Cells.
- Author
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Mayorga-Flores M, Chantôme A, Melchor-Meneses CM, Domingo I, Titaux-Delgado GA, Galindo-Murillo R, Vandier C, and Del Río-Portilla F
- Abstract
Peptide-based therapy against cancer is a field of great interest for biomedical developments. Since it was shown that SK3 channels promote cancer cell migration and metastatic development, we started using these channels as targets for the development of antimetastatic drugs. Particularly, tamapin (a peptide found in the venom of the scorpion Mesobuthus tamulus ) is the most specific toxin against the SK2 channel currently known. Considering this fact, we designed diverse tamapin mutants based on three different hypotheses to discover a new potent molecule to block SK3 channels. We performed in vitro studies to evaluate this new toxin derivative inhibitor of cancer cell migration. Our results can be used to generate a new tamapin-based therapy against cancer cells that express SK3 channels., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
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32. Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression.
- Author
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Bery F, Figiel S, Kouba S, Fontaine D, Guéguinou M, Potier-Cartereau M, Vandier C, Guibon R, Bruyère F, Fromont G, and Mahéo K
- Subjects
- Cell Line, Tumor, Cell Movement, Eicosapentaenoic Acid pharmacology, Glycolipids pharmacology, Humans, Linoleic Acid pharmacology, Male, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Small-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Epithelial-Mesenchymal Transition, Hypoxia physiopathology, Prostatic Neoplasms pathology, Small-Conductance Calcium-Activated Potassium Channels metabolism, Tumor Microenvironment, Zinc Finger E-box-Binding Homeobox 1 metabolism
- Abstract
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca
2+ -activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.- Published
- 2020
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33. Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease.
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Fontaine D, Figiel S, Félix R, Kouba S, Fromont G, Mahéo K, Potier-Cartereau M, Chantôme A, and Vandier C
- Subjects
- Animals, Humans, Ether chemistry, Fatty Acids, Unsaturated metabolism, Ion Channels metabolism
- Abstract
Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage [i.e., plasmalogens (Pls)] at the sn 1 position of the glycerol backbone, and they are enriched in PUFAs at the sn 2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs) and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions., (Copyright © 2020 Fontaine et al.)
- Published
- 2020
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34. Lipidic synthetic alkaloids as SK3 channel modulators. Synthesis and biological evaluation of 2-substituted tetrahydropyridine derivatives with potential anti-metastatic activity.
- Author
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Kouba S, Braire J, Félix R, Chantôme A, Jaffrès PA, Lebreton J, Dubreuil D, Pipelier M, Zhang X, Trebak M, Vandier C, Mathé-Allainmat M, and Potier-Cartereau M
- Subjects
- Alkaloids chemical synthesis, Alkaloids chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HEK293 Cells, Humans, Lipids chemistry, Molecular Structure, Pyrrolidines chemical synthesis, Pyrrolidines chemistry, Structure-Activity Relationship, Alkaloids pharmacology, Antineoplastic Agents pharmacology, Lipids pharmacology, Pyrrolidines pharmacology, Small-Conductance Calcium-Activated Potassium Channels metabolism
- Abstract
Small Conductance Calcium (Ca
2+ )-activated potassium (K+ ) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer., (Copyright © 2019. Published by Elsevier Masson SAS.)- Published
- 2020
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35. Ca 2+ channels in cancer.
- Author
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Gautier M, Trebak M, Fleig A, Vandier C, and Ouadid-Ahidouch H
- Subjects
- Animals, Calcium Channels metabolism, Calcium Signaling, Humans, Calcium metabolism, Neoplasms metabolism
- Published
- 2019
- Full Text
- View/download PDF
36. Ca 2+ homeostasis and cancer.
- Author
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Gautier M, Trebak M, Fleig A, Vandier C, and Ouadid-Ahidouch H
- Subjects
- Animals, Calcium Signaling, Carcinogenesis, Cellular Microenvironment, Homeostasis, Humans, Neoplasms, Calcium metabolism, Calcium Channels metabolism
- Published
- 2019
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- View/download PDF
37. A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy.
- Author
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Figiel S, Bery F, Chantôme A, Fontaine D, Pasqualin C, Maupoil V, Domingo I, Guibon R, Bruyère F, Potier-Cartereau M, Vandier C, Fromont G, and Mahéo K
- Abstract
The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, we identified a new signaling pathway with a positive feedback loop between the epithelial-to-mesenchymal transition (EMT) transcription factor Zeb1 and the Ca
2+ -activated K+ channel SK3, which leads to an amplification of Ca2+ entry and cellular migration. Using in vitro experiments and ex vivo cultures of human PCa slices, we demonstrated that LA and EPA exert anticancer effects, by modulating Ca2+ entry, which was involved in Zeb1 regulation and cancer cellular migration. This functional approach using human prostate tumors highlights the clinical relevance of our observations, and may allow us to consider the possibility of targeting cancer spread by altering the lipid microenvironment., Competing Interests: The authors declare no conflicts of interest.- Published
- 2019
- Full Text
- View/download PDF
38. Lipid metabolism and Calcium signaling in epithelial ovarian cancer.
- Author
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Kouba S, Ouldamer L, Garcia C, Fontaine D, Chantome A, Vandier C, Goupille C, and Potier-Cartereau M
- Subjects
- Animals, Arachidonic Acid metabolism, Calcium Signaling, Carcinogenesis, Epithelial Cells pathology, Female, Humans, Lipid Metabolism, Lysophospholipids metabolism, Ovarian Neoplasms pathology, Receptor Cross-Talk, Risk, Epithelial Cells metabolism, Ovarian Neoplasms metabolism
- Abstract
Epithelial Ovarian cancer (EOC) is the deadliest gynecologic malignancy and represents the fifth leading cause of all cancer-related deaths in women. The majority of patients are diagnosed at an advanced stage of the disease that has spread beyond the ovaries to the peritoneum or to distant organs (stage FIGO III-IV) with a 5-year overall survival of about 29%. Consequently, it is necessary to understand the pathogenesis of this disease. Among the factors that contribute to cancer development, lipids and ion channels have been described to be associated to cancerous diseases particularly in breast, colorectal and prostate cancers. Here, we reviewed the literature data to determine how lipids or lipid metabolites may influence EOC risk or progression. We also highlighted the role and the expression of the calcium (Ca
2+ ) and calcium-activated potassium (KCa) channels in EOC and how lipids might regulate them. Although lipids and some subclasses of nutritional lipids may be associated to EOC risk, lipid metabolism of LPA (lysophosphatidic acid) and AA (arachidonic acid) emerges as an important signaling network in EOC. Clinical data showed that they are found at high concentrations in EOC patients and in vitro and in vivo studies referred to them as triggers of the Ca2+ entry in the cancer cells inducing their proliferation, migration or drug resistance. The cross-talk between lipid mediators and Ca2+ and/or KCa channels needs to be elucidated in EOC in order to facilitate the understanding of its outcomes and potentially suggest novel therapeutic strategies including treatment and prevention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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39. Functional Organotypic Cultures of Prostate Tissues: A Relevant Preclinical Model that Preserves Hypoxia Sensitivity and Calcium Signaling.
- Author
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Figiel S, Pasqualin C, Bery F, Maupoil V, Vandier C, Potier-Cartereau M, Domingo I, Guibon R, Bruyere F, Maheo K, and Fromont G
- Subjects
- Aged, Antigens, Neoplasm metabolism, Carbonic Anhydrase IX metabolism, Cell Hypoxia, Humans, Kallikreins metabolism, Male, Middle Aged, Neoplasm Proteins metabolism, Prostate-Specific Antigen metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Tissue Culture Techniques, Transcriptional Regulator ERG metabolism, Zinc Finger E-box-Binding Homeobox 1 metabolism, Calcium metabolism, Calcium Signaling, Models, Biological, Prostatic Neoplasms metabolism, Tumor Microenvironment
- Abstract
In prostate cancer research, there is a lack of valuable preclinical models. Tumor cell heterogeneity and sensitivity to microenvironment signals, such as hypoxia or extracellular calcium concentration, are difficult to reproduce. Here, we developed and characterized an ex vivo tissue culture model preserving these properties. Prostate tissue slices from 26 patients were maintained ex vivo under optimized culture conditions. The expression of markers associated with proliferation, androgen-receptor signaling, and hypoxia was assessed by immunostaining. A macroscope was used to achieve real-time calcium fluorescence optical imaging. Tissue morphology was maintained successfully without necrosis for 5 days. Compared with native tumors and tissue cultured with androgens, androgen deprivation in the medium led to decreased expression of both androgen receptor and its target gene products, prostate specific antigen (PSA) and ETS-related gene (ERG). Ex vivo cultured slices also were sensitive to hypoxia because carbonic anhydrase IX and zinc finger E-box binding homeobox 1 (Zeb1) protein levels increased in 1% oxygen. Exposure of slices to supraphysiological extracellular Ca
2+ concentration induced a robust and rapid Ca2+ entry, with a greater response in tumor compared with nontumor tissue. This ex vivo model reproduces the morphologic and functional characteristics of human prostate cancer, including sensitivity to androgen deprivation and induced response to hypoxia and extracellular Ca2+ . It therefore could become an attractive tool for drug response prediction studies., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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40. STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia.
- Author
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Debant M, Burgos M, Hemon P, Buscaglia P, Fali T, Melayah S, Le Goux N, Vandier C, Potier-Cartereau M, Pers JO, Tempescul A, Berthou C, Bagacean C, Mignen O, and Renaudineau Y
- Subjects
- Aged, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological therapeutic use, B-Lymphocytes cytology, B-Lymphocytes immunology, B-Lymphocytes metabolism, Calcium immunology, Calcium metabolism, Calcium Signaling immunology, Cell Membrane metabolism, Cell Survival drug effects, Cell Survival immunology, Disease Progression, Female, Gene Knockdown Techniques, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, ORAI1 Protein antagonists & inhibitors, ORAI1 Protein genetics, ORAI1 Protein immunology, ORAI1 Protein metabolism, Primary Cell Culture, Prospective Studies, RNA, Small Interfering metabolism, Stromal Interaction Molecule 1 genetics, Stromal Interaction Molecule 1 metabolism, TRPC Cation Channels genetics, TRPC Cation Channels immunology, TRPC Cation Channels metabolism, Treatment Outcome, Tumor Cells, Cultured, Antineoplastic Agents, Immunological pharmacology, B-Lymphocytes drug effects, Calcium Signaling genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Neoplasm Proteins antagonists & inhibitors, Stromal Interaction Molecule 1 antagonists & inhibitors
- Abstract
Background: Dysregulation in calcium (Ca
2+ ) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca2+ pathway has been associated with disease progression, the importance of the newly described constitutive Ca2+ entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca2+ actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study., Methods: An extensive analysis of the Ca2+ entry (CE) pathway in CLL B cells was performed including constitutive Ca2+ entry, basal Ca2+ levels, and store operated Ca2+ entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients., Results: Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca2+ concentrations; (iii) independent from the BCR-PLCγ2-InsP3 R (SOCE) Ca2+ signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1PM ); and (vi) blocked when using a mAb targeting STIM1PM . Next, we further established an association between an elevated expression of STIM1PM and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1PM CLL subgroup., Conclusions: These data establish the critical role of a newly discovered BCR independent Ca2+ entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane.- Published
- 2019
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41. Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer.
- Author
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Ibrahim S, Dakik H, Vandier C, Chautard R, Paintaud G, Mazurier F, Lecomte T, Guéguinou M, and Raoul W
- Abstract
Background : Colorectal cancer (CRC) is a highly devastating cancer. Ca
2+ -dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca2+ channels and Ca2+ -dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods : We selected a total of 35 genes covering KCa channels KCNN 1 - 4 , KCNMA1 and their subunits KCNMB 1 - 4 , endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2 , Ca2+ channels ORAI 1 - 3 and the family of cation channels TRP ( TRPC 1 - 7 , TRPA1, TRPV1/2, 4 - 6 and TRPM 1 - 8 ). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results : KCNN4 and TRPM 2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca2+ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca2+ channels remodeling in CRC., Competing Interests: The authors declare no conflict of interest.- Published
- 2019
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42. SK3 Gene Polymorphism Is Associated with Taxane Neurotoxicity and Cell Calcium Homeostasis.
- Author
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Rua C, Guéguinou M, Soubai I, Viel E, Potier-Cartereau M, Chantome A, Barbe C, Bougnoux P, Barin-Le Guellec C, and Vandier C
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Biological Transport, Calcium Signaling drug effects, Cell Line, Female, Homeostasis, Humans, Male, Middle Aged, Peripheral Nervous System Diseases metabolism, Sequence Analysis, DNA, Taxoids therapeutic use, Calcium metabolism, Genetic Predisposition to Disease, Peripheral Nervous System Diseases etiology, Pharmacogenomic Variants, Polymorphism, Genetic, Small-Conductance Calcium-Activated Potassium Channels genetics, Taxoids adverse effects
- Abstract
Purpose: Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorating its long-term course has been identified. The physiology of taxane neuropathy is not clear, and diverse mechanisms have been suggested, with ion channels regulating Ca
2+ homeostasis appearing good candidates. The calcium-activated potassium channel SK3 is encoded by the KCNN3 gene, which is characterized by a length polymorphism due to variable number of CAG repeats. Experimental Design: To study the influence of the polymorphism of CAG motif repeat of KCNN3 on the development of taxane-induced neuropathy, we evaluated 176 patients treated with taxanes for breast cancer. In parallel, we measured Ca2+ entry using Fura2-AM dye in HEK cells expressing short versus long CAG alleles of KCNN3 Results: In the current study, we report that in the presence of docetaxel, Ca2+ entry was significantly increased in cells expressing short versus long CAG alleles of SK3 and that a SK3-lipid blocker inhibits this effect. We found that patients carrying a short KCNN3 allele exhibited significantly increased incidence of taxane neuropathy compared with those carrying longer alleles. Conclusions: The clinical implication of these findings is that KCNN3 polymorphism may increase patient susceptibility to taxane neurotoxicity and that the use of SK3 blockers during taxanes' administration may represent an interesting approach for the prevention of this neurotoxicity. Clin Cancer Res; 24(21); 5313-20. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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43. Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity.
- Author
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Anon B, Largeau B, Girault A, Chantome A, Caulet M, Perray C, Moussata D, Vandier C, Barin-Le Guellec C, and Lecomte T
- Subjects
- Adult, Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Fluorouracil administration & dosage, HEK293 Cells, Humans, Leucovorin administration & dosage, Male, Middle Aged, Neurotoxicity Syndromes blood, Neurotoxicity Syndromes etiology, Organoplatinum Compounds administration & dosage, Oxaliplatin administration & dosage, Patch-Clamp Techniques, Polymorphism, Genetic, Trinucleotide Repeats, Neurotoxicity Syndromes genetics, Oxaliplatin adverse effects, Small-Conductance Calcium-Activated Potassium Channels genetics
- Abstract
Introduction: Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN., Materials and Methods: We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin., Results: There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups., Conclusion: We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.
- Published
- 2018
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44. Regulation of human dendritic cell immune functions by ion channels.
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Vandier C and Velge-Roussel F
- Subjects
- Animals, Calcium Release Activated Calcium Channels genetics, Calcium Release Activated Calcium Channels metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Cell Movement genetics, Cell Movement immunology, Dendritic Cells cytology, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels genetics, Intermediate-Conductance Calcium-Activated Potassium Channels metabolism, Ion Channels genetics, Transient Receptor Potential Channels genetics, Transient Receptor Potential Channels metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Immunity genetics, Immunomodulation genetics, Ion Channels metabolism
- Abstract
Dendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) able to induce both specific immunity and immune tolerance. Using information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. The remarkable ability of these cells to induce, enhance and orient the immune response, while at the same time maintaining self-tolerance, makes them key players in the immune system. Despite the fact that the role of Ca
2+ has been clearly established in human DC functions, the link between ion homeostasis, mainly Ca2+ , and DC functions is not fully understood. After all, a growing number of works clearly show the role of SOCE and associated channels in the maturation step, and those of K+ channels in migration. This review highlights the key papers published over the past few years and summarizes prospects for the near future., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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45. Synthesis of Alkyl-Glycerolipids Standards for Gas Chromatography Analysis: Application for Chimera and Shark Liver Oils.
- Author
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Pinault M, Guimaraes C, Couthon H, Thibonnet J, Fontaine D, Chantôme A, Chevalier S, Besson P, Jaffrès PA, and Vandier C
- Subjects
- Animals, Chromatography, Gas standards, Fish Oils chemistry, Glycerides chemical synthesis, Liver chemistry, Sharks
- Abstract
Natural O -alkyl-glycerolipids, also known as alkyl-ether-lipids (AEL), feature a long fatty alkyl chain linked to the glycerol unit by an ether bond. AEL are ubiquitously found in different tissues but, are abundant in shark liver oil, breast milk, red blood cells, blood plasma, and bone marrow. Only a few AEL are commercially available, while many others with saturated or mono-unsaturated alkyl chains of variable length are not available. These compounds are, however, necessary as standards for analytical methods. Here, we investigated different reported procedures and we adapted some of them to prepare a series of 1- O -alkyl-glycerols featuring mainly saturated alkyl chains of various lengths (14:0, 16:0, 17:0, 19:0, 20:0, 22:0) and two monounsaturated chains (16:1, 18:1). All of these standards were fully characterized by NMR and GC-MS. Finally, we used these standards to identify the AEL subtypes in shark and chimera liver oils. The distribution of the identified AEL were: 14:0 (20-24%), 16:0 (42-54%) and 18:1 (6-16%) and, to a lesser extent, (0.2-2%) for each of the following: 16:1, 17:0, 18:0, and 20:0. These standards open the possibilities to identify AEL subtypes in tumours and compare their composition to those of non-tumour tissues., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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46. Singular Interaction between an Antimetastatic Agent and the Lipid Bilayer: The Ohmline Case.
- Author
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Herrera FE, Sevrain CM, Jaffrès PA, Couthon H, Grélard A, Dufourc EJ, Chantôme A, Potier-Cartereau M, Vandier C, and Bouchet AM
- Abstract
SK3 channels are abnormaly expressed in metastatic cells, and Ohmline (OHM), an ether lipid, has been shown to reduce the activity of SK3 channels and the migration capacity of cancer cells. OHM incorporation into the plasma membrane is proposed to dissociate the protein complex formed between SK3 and Orai1, a potassium and a calcium channel, respectively, and would lead to a modification in the lipid environment of both the proteins. Here, we report the synthesis of deuterated OHM that affords the determination, through solid-state NMR, of its entire partitioning into membranes mimicking the SK3 environment. Use of deuterated lipids affords the demonstration of an OHM-induced membrane disordering, which is dose-dependent and increases with increasing amounts of cholesterol (CHOL). Molecular dynamics simulations comfort the disordering action and show that OHM interacts with the carbonyl and phosphate groups of stearoylphosphatidylcholine and sphingomyelin and to a minor extent with CHOL. OHM is thus proposed to remove the CHOL OH moieties away from their main binding sites, forcing a new rearrangement with other lipid groups. Such an interaction takes its origin at the lipid-water interface, but it propagates toward the entire lipid molecules and leads to a cooperative destabilization of the lipid acyl chains, that is, membrane disordering. The consequences of this reorganization of the lipid phases are discussed in the context of the OHM-induced inhibition of SK3 channels., Competing Interests: The authors declare no competing financial interest.
- Published
- 2017
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47. Ca 2+ protein alpha 1D of CaV1.3 regulates intracellular calcium concentration and migration of colon cancer cells through a non-canonical activity.
- Author
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Fourbon Y, Guéguinou M, Félix R, Constantin B, Uguen A, Fromont G, Lajoie L, Magaud C, Lecomte T, Chamorey E, Chatelier A, Mignen O, Potier-Cartereau M, Chantôme A, Bois P, and Vandier C
- Subjects
- Active Transport, Cell Nucleus, Cell Membrane metabolism, Cell Nucleus metabolism, Colonic Neoplasms physiopathology, Cytosol metabolism, Electrophysiological Phenomena, Endoplasmic Reticulum metabolism, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Sodium-Calcium Exchanger metabolism, Calcium metabolism, Calcium Channels, L-Type chemistry, Calcium Channels, L-Type metabolism, Cell Movement, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Intracellular Space metabolism
- Abstract
It is generally accepted that voltage-gated Ca
2+ channels, CaV, regulate Ca2+ homeostasis in excitable cells following plasma membrane depolarization. Here, we show that the Ca2+ protein α1D of CaV1.3 channel is overexpressed in colorectal cancer biopsies compared to normal tissues. Gene silencing experiments targeting α1D reduced the migration and the basal cytosolic Ca2+ concentration of HCT116 colon cancer cell line and modified the cytosolic Ca2+ oscillations induced by the sodium/calcium exchanger NCX1/3 working in its reverse mode. Interestingly, NCX1/3 regulated membrane potential of HCT116 cells only when α1D was silenced, and blocking NCX1/3 increased cytosolic Ca2+ concentration and cell migration. However, membrane depolarization did not induce an increase in intracellular Ca2+ . Patch-clamp experiments clearly showed that the inward Ca2+ current was absent. Finally, flow cytometry and immunofluorescence studies showed that α1D protein was localized at the plasma membrane, in cytosol and cell nuclei. Altogether, we uncover a novel signaling pathway showing that α1D is involved in the regulation of Ca2+ homeostasis and cell migration by a mechanism independent of its plasma membrane canonical function but that involved plasma membrane Na+ /Ca2+ exchanger.- Published
- 2017
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48. Constitutive calcium entry and cancer: updated views and insights.
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Mignen O, Constantin B, Potier-Cartereau M, Penna A, Gautier M, Guéguinou M, Renaudineau Y, Shoji KF, Félix R, Bayet E, Buscaglia P, Debant M, Chantôme A, and Vandier C
- Subjects
- Animals, Calcium Signaling, Humans, Neoplasms pathology, Calcium metabolism, Neoplasms metabolism
- Abstract
Tight control of basal cytosolic Ca
2+ concentration is essential for cell survival and to fine-tune Ca2+ -dependent cell functions. A way to control this basal cytosolic Ca2+ concentration is to regulate membrane Ca2+ channels including store-operated Ca2+ channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca2+ channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca2+ channels contributes to Ca2+ entry and the transient increase in cytosolic Ca2+ concentration involved in intracellular signaling. However, in various experimental conditions, Ca2+ entry and/or Ca2+ currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca2+ channels are already open/activated in basal condition, contributing therefore to constitutive Ca2+ entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities.- Published
- 2017
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49. Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy.
- Author
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Jaffrès PA, Gajate C, Bouchet AM, Couthon-Gourvès H, Chantôme A, Potier-Cartereau M, Besson P, Bougnoux P, Mollinedo F, and Vandier C
- Subjects
- Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Movement drug effects, Drug Design, Glycolipids adverse effects, Glycolipids chemistry, Humans, Ion Channels metabolism, Membrane Microdomains metabolism, Membrane Microdomains pathology, Molecular Structure, Neoplasm Invasiveness, Neoplasms metabolism, Neoplasms pathology, Phospholipid Ethers adverse effects, Phospholipid Ethers chemistry, Signal Transduction drug effects, Structure-Activity Relationship, Antineoplastic Agents therapeutic use, Glycolipids therapeutic use, Ion Channels drug effects, Membrane Microdomains drug effects, Neoplasms drug therapy, Phospholipid Ethers therapeutic use
- Abstract
Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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50. In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis.
- Author
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Henry CO, Dalloneau E, Pérez-Berezo MT, Plata C, Wu Y, Guillon A, Morello E, Aimar RF, Potier-Cartereau M, Esnard F, Coraux C, Börnchen C, Kiefmann R, Vandier C, Touqui L, Valverde MA, Cenac N, and Si-Tahar M
- Subjects
- A549 Cells, Animals, Calcium Signaling, Cystic Fibrosis immunology, Cystic Fibrosis pathology, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Female, Humans, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Rats, Sprague-Dawley, Alveolar Epithelial Cells metabolism, Cystic Fibrosis metabolism, TRPV Cation Channels physiology
- Abstract
Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
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