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Differential Effects of Gonadotropin-Releasing Hormone (GnRH)-I and GnRH-II on Prostate Cancer Cell Signaling and Death

Hormone Research Center (K.M., D.Y.O., J.S.M., S.A., J.H.L., D.G.B., H.-S.P., K.L., Y.C.L., H.B.K., J.Y.S.) and School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; Neurogenex Co. Ltd. (N.C.J.), Biotechnology Incubating Center Golden Helix, Seoul National University, Seoul 151-744, Republic of Korea; School of Biological Sciences (K.K.), Seoul National University, Seoul 151-742, Republic of Korea; Institut National de la Santé et de la Recherche Médicale U413, Laboratory of Cellular and Molecular Neuroendocrinology (H.V.), European Institute for Peptide Research, University of Rouen, 76821 Mont-Saint-Aignan, France; and Laboratory of G Protein Coupled Receptors (J.Y.S.), Korea University College of Medicine, Seoul 136-705, Republic of Korea

Address all correspondence and requests for reprints to: Jae Young Seong, Ph.D., Laboratory of G Protein Coupled Receptors, Korea University College of Medicine, Seoul 136-705, Republic of Korea. E-mail: jyseong{at}korea.ac.kr; or Hyuk Bang Kwon, Ph.D., Hormone Research Center and School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea. E-mail: kwnohb{at}chonnam.ac.kr.

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 Ca²⁺ concentration ([Ca²⁺]_i) either through Ca²⁺ influx from external Ca²⁺ source or via mobilization of Ca²⁺ from internal Ca²⁺ stores. Interestingly, the [Ca²⁺]_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 [Ca²⁺]_i increase. Concurrently at high concentrations, trptorelix-1 and cetrorelix inhibited GnRH-I-induced [Ca²⁺]_i increase, whereas at low concentrations they exerted an agonistic action, inducing Ca²⁺ influx. High concentrations of trptorelix-1 but not cetrorelix-induced prostate cancer cell death, probably through an apoptotic process. Using photoaffinity labeling with ¹²⁵I-[azidobenzoyl-D-Lys⁶]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.

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