Differential effects of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on prostate cancer cell signaling and death

J Clin Endocrinol Metab. 2005 Jul;90(7):4287-98. doi: 10.1210/jc.2004-1894. Epub 2005 May 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Calcium / metabolism
  • Gonadotropin-Releasing Hormone / analogs & derivatives*
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Gonadotropin-Releasing Hormone / pharmacology*
  • Humans
  • Inositol Phosphates / metabolism
  • Male
  • Photoaffinity Labels
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, LHRH / analysis
  • Receptors, LHRH / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ryanodine Receptor Calcium Release Channel / drug effects
  • Signal Transduction / physiology*


  • GNRHR2 protein, human
  • Inositol Phosphates
  • Photoaffinity Labels
  • Receptors, LHRH
  • Ryanodine Receptor Calcium Release Channel
  • Gonadotropin-Releasing Hormone
  • LHRH, His(5)-Trp(7)-Tyr(8)-
  • Calcium