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

AbstractCONTEXT:
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.
AuthorsKaushik Maiti, D Y Oh, Da Young Oh, Jung Sun Moon, Sujata Acharjee, Jian Hua Li, Dong Gyu Bai, Hee-Sae Park, Keesook Lee, Young Chul Lee, Neon Chul Jung, Kyungjin Kim, Hubert Vaudry, Hyuk Bang Kwon, Jae Young Seong
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 90 Issue 7 Pg. 4287-98 (Jul 2005) ISSN: 0021-972X [Print] United States
PMID15870130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • Apoptosis
  • Calcium (metabolism)
  • Gonadotropin-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, pharmacology)
  • Humans
  • Inositol Phosphates (metabolism)
  • Male
  • Photoaffinity Labels
  • Prostatic Neoplasms (metabolism, pathology)
  • Receptors, LHRH (analysis, physiology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ryanodine Receptor Calcium Release Channel (drug effects)
  • Signal Transduction (physiology)

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