CONTEXT: GnRH is known to directly regulate prostate cancer cell proliferation, but the precise mechanism of action of the peptide is still under investigation. OBJECTIVE: This study demonstrates differential effects of GnRH-I and GnRH-II on androgen-independent human prostate cancer cells. RESULTS: Both GnRH-I and GnRH-II increased the intracellular Ca(2+) concentration ([Ca(2+)](i)) either through Ca(2+) influx from external Ca(2+) source or via mobilization of Ca(2+) from internal Ca(2+) stores. Interestingly, the [Ca(2+)](i) increase was mediated by activation of the ryanodine receptor but not the inositol trisphosphate receptor. Trptorelix-1, a novel GnRH-II antagonist but not cetrorelix, a classical GnRH-I antagonist, completely inhibited the GnRH-II-induced [Ca(2+)](i) increase. Concurrently at high concentrations, trptorelix-1 and cetrorelix inhibited GnRH-I-induced [Ca(2+)](i) increase, whereas at low concentrations they exerted an agonistic action, inducing Ca(2+) influx. High concentrations of trptorelix-1 but not cetrorelix-induced prostate cancer cell death, probably through an apoptotic process. Using photoaffinity labeling with (125)I-[azidobenzoyl-D-Lys(6)]GnRH-II, we observed that an 80-kDa protein specifically bound to GnRH-II. CONCLUSIONS: This study suggests the existence of a novel GnRH-II binding protein, in addition to a conventional GnRH-I receptor, in prostate cancer cells. These data may facilitate the development of innovatory therapeutic drugs for the treatment of prostate cancer.
CONTEXT: GnRH is known to directly regulate prostate cancer cell proliferation, but the precise mechanism of action of the peptide is still under investigation. OBJECTIVE: This study demonstrates differential effects of GnRH-I and GnRH-II on androgen-independent humanprostate cancer cells. RESULTS: Both GnRH-I and GnRH-II increased the intracellular Ca(2+) concentration ([Ca(2+)](i)) either through Ca(2+) influx from external Ca(2+) source or via mobilization of Ca(2+) from internal Ca(2+) stores. Interestingly, the [Ca(2+)](i) increase was mediated by activation of the ryanodine receptor but not the inositol trisphosphate receptor. Trptorelix-1, a novel GnRH-II antagonist but not cetrorelix, a classical GnRH-I antagonist, completely inhibited the GnRH-II-induced [Ca(2+)](i) increase. Concurrently at high concentrations, trptorelix-1 and cetrorelix inhibited GnRH-I-induced [Ca(2+)](i) increase, whereas at low concentrations they exerted an agonistic action, inducing Ca(2+) influx. High concentrations of trptorelix-1 but not cetrorelix-induced prostate cancer cell death, probably through an apoptotic process. Using photoaffinity labeling with (125)I-[azidobenzoyl-D-Lys(6)]GnRH-II, we observed that an 80-kDa protein specifically bound to GnRH-II. CONCLUSIONS: This study suggests the existence of a novel GnRH-II binding protein, in addition to a conventional GnRH-I receptor, in prostate cancer cells. These data may facilitate the development of innovatory therapeutic drugs for the treatment of prostate cancer.
Authors: Amy T Desaulniers; Rebecca A Cederberg; Clay A Lents; Brett R White Journal: Front Endocrinol (Lausanne) Date: 2017-12-11 Impact factor: 5.555