Type I gonadotropin-releasing hormone receptor mediates the antiproliferative effects of GnRH-II on prostate cancer cells.
BACKGROUND
GnRH-II has been shown to exert a strong antiproliferative action on tumors of the female reproductive system. The data so far reported on the effects of GnRH-II on prostate cancer growth are controversial. Moreover, it is still unclear through which receptor [type I or type II GnRH-receptor (GnRH-R)] GnRH-II might modulate cancer cell proliferation.


OBJECTIVE
The objective of this work was to investigate whether GnRH-II might affect the proliferation of prostate cancer cells and to identify the GnRH-R through which the peptide might exert its activity.


METHODS
We investigated the effects of GnRH-II on prostate cancer cell proliferation. We then transfected PC3 cells with a small interfering RNA targeted to type I GnRH-R. After receptor silencing we evaluated the effects of GnRH-II on cell proliferation and on forskolin-induced intracellular cAMP accumulation. Similar experiments were performed by silencing type II GnRH-R.


RESULTS
GnRH-II exerted an antiproliferative activity on prostate cancer cells. Transfection of PC3 cells with a type I GnRH-R small interfering RNA resulted in a significant decrease of the expression of this receptor. After type I GnRH-R silencing: 1) the antiproliferative effect of GnRH-II was completely abrogated; and 2) GnRH-II lost its capacity to counteract the forskolin-induced cAMP accumulation. On the contrary, type II GnRH-R silencing did not counteract the antiproliferative effect of GnRH-II.


CONCLUSIONS
GnRH-II exerts a specific and significant antiproliferative action on prostate cancer cells. This antitumor effect is mediated by the activation of type I (but not of type II) GnRH-R and by its coupled cAMP intracellular signaling pathway.
Montagnani Marelli
Marina
M
Center of Endocrinological Oncology, Department of Endocrinology, Physiopathology and Applied Biology, University of Milano, 20133 Milano, Italy.
Moretti
Roberta M
RM
Mai
Stefania
S
Januszkiewicz-Caulier
Joanna
J
Motta
Marcella
M
Limonta
Patrizia
P
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000502:physiology; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011966:Receptors, LHRH / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C484844:GNRHR protein, human; C427484:GNRHR2 protein, human; D034741:RNA, Small Interfering; D011966:Receptors, LHRH; D000242:Cyclic AMP