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Involvement of Ion Channels in Endothelin-1-induced Signalling in Human Prostate Cancer Cells
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Edité par CCSD -
International audience. Objective: Endothelin-1 (ET-1), a potent vasoconstrictor secreted primarily by endothelial and various epithelial cancercells has been implicated in prostate cancer progression and the ET axis has been suggested to represent a novel andexciting target in the treatment of prostate cancer (PCa). ET-1, acting primarily through the endothelin receptors (ETRs)is integrally involved in multiple facets of PCa progression, including cell growth, inhibition of apoptosis, angiogenesis anddevelopment of bone metastases. ET-1 and ETRs are expressed in PCa tissues and their expression is modulated duringthe evolution of these cancers. The purpose of the present work was to study the effects of ET-1 on proliferation of humanPCa cells PC-3 and the mechanisms by which the activation of ETRs may promote the PCa cells growth.Methods: Prostate cancer cell lines and primary cultured epithelial cells from prostate cancer, RT-PCR and calciumimaging techniques were used to study the expression and functionality of the Endothelin receptors and involvement ofion channels in the effects of ET-1 in prostate cancer cells.Results: We show for the first time that the application of ET-1 induces a dose-dependent cell proliferation andan increase in intracellular free Ca2+ concentrations ([Ca2+]i) via a mobilisation of the internal calcium stores and bya capacitative calcium entry (CCE). These effects of ET-1 were completely abolished by BQ123, a selective ETARantagonist, but not by BQ788, a selective ETBR antagonist. By use of pharmacological inhibitors and siRNA targetingcalcium-activated (IKCa1 and BKCa) potassium channels and calcium channels (TRPC1, TRPV6, Orai1), we showedthat these ion channels play an important role in calcium entry and cell proliferation induced by ET-1 in PCa cells.Conclusion: These results suggest that these ions channels evidenced here might constitute potential targets toblock the ET axis in human prostate cancers.
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