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Type I Gonadotropin-Releasing Hormone Receptor Mediates the Antiproliferative Effects of GnRH-II on Prostate Cancer Cells

Center of Endocrinological Oncology (M.M.M., R.M.M., S.M., M.M., P.L.), Department of Endocrinology, Physiopathology and Applied Biology, University of Milano, 20133 Milano, Italy; and Department of Endocrinology and Metabolic Diseases (J.J.-C.), Medical University of Lodz, 93-338 Lodz, Poland

Address all correspondence and requests for reprints to: Patrizia Limonta, Ph.D., Center of Endocrinological Oncology, University of Milano, Via Balzaretti 9, Milano, Italy. E-mail: patrizia.limonta{at}unimi.it.

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.

Design: 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.