Effects of the luteinising hormone-releasing hormone (LH-RH) agonist leuprolide on adenylyl cyclase regulation through G-protein coupled receptors inrat ventral prostate

Luteinising hormone-releasing hormone (LH-RH) agonists are widely used for the therapy of advanced prostate cancer through the suppression of testoste rone secretion. Furthermore, recent studies indicate the existence of prost ate LH-RH receptors coupled to signalling pathways resulting in direct anti proliferative effects. In order to shed light on the mechanisms through whi ch these compounds inhibit prostate cell growth, we investigated the effect s of leuprolide (a LH-RH agonist) treatment of rats compared with the effec ts of surgical castration on the behaviour of G-protein coupled receptors a cting through adenylyl cyclase in the ventral prostate. Important decreases of both plasma testosterone levels and ventral prostate weight were observ ed 5 weeks after subcutaneous (s.c.) injection of a leuprolide-depot prepar ation (1.5 mg/kg body weight (b.w.)) or 5 days after bilateral gonadectomy. However, leuprolide treatment increased the number of vasoactive intestina l peptide (VIP) receptors and the ability of this neuropeptide to stimulate adenylyl cyclase activity in prostate membranes, whereas surgical castrati on decreased both parameters. Moreover, leuprolide resulted in significant increases of prostate alpha (s) and alpha (i1-3) (but not alpha (i1) and be ta) G-protein levels, while the four G-protein subunits were overexpressed after gonadectomy. The estimation of alpha (s) and alpha (i) activity by ex prriments with Gpp[NH]p and forskolin indicated a potentiation of the two a rms of adenylyl cyclase regulation in leuprolide-treated rats. Present obse rvations suggest that leuprolide treatment leads to an antimitogenic respon se by acting mainly through the activation of Gi proteins negatively couple d to adenylyl cyclase. (C) 2001 Elsevier Science Ltd. All rights reserved.