Differential effects of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on prostate cancer cell signaling and death.
BACKGROUND
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.
Maiti
Kaushik
K
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Oh
D Y
DY
Oh
Da Young
DY
Moon
Jung Sun
JS
Acharjee
Sujata
S
Li
Jian Hua
JH
Bai
Dong Gyu
DG
Park
Hee-Sae
HS
Lee
Keesook
K
Lee
Young Chul
YC
Jung
Neon Chul
NC
Kim
Kyungjin
K
Vaudry
Hubert
H
Kwon
Hyuk Bang
HB
Seong
Jae Young
JY
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D019920:Photoaffinity Labels; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011966:Receptors, LHRH / Q000032:analysis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*
C427484:GNRHR2 protein, human; D007295:Inositol Phosphates; D019920:Photoaffinity Labels; D011966:Receptors, LHRH; D019837:Ryanodine Receptor Calcium Release Channel; D007987:Gonadotropin-Releasing Hormone; C047717:LHRH, His(5)-Trp(7)-Tyr(8)-; D002118:Calcium