Gonadotropin-releasing hormone in apoptosis of prostate cancer cells

GnRH and its analogs (GnRH-a) are used extensively for the treatment of prostate cancer and other hormone-dependent diseases via the desensitization of pituitary gonadotropes, which consequently leads to the inhibition of gonadotropins, gonadal steroids and tumor growth. The actions of GnRH-a are mediated by the GnRH receptor (GnRHR) that is expressed in both the pituitary and extrapituitary sites, including normal tissues and tumors. Several studies have provided evidence that besides its pituitary effects, GnRH-a may exert direct anti-proliferative and apoptotic effects in tumor cells. These effects are mediated by the GnRHRs via signal transduction mechanisms that are distinct from the classical pituitary mechanisms. Here we describe the direct effects of GnRH-a on prostate cancer and other types of cancer. Interestingly, androgen ablation by GnRH-a is the main treatment for hormone-dependent prostate cancer. However, most of these tumors become eventually hormone-refractory, and are no longer sensitive to the GnRH-a-mediated reduction in androgen levels. Hence, the ability of GnRH-a to induce direct effects such as apoptosis may have large implications regarding the clinical use of GnRH-a. Therefore, an understanding of the cellular mechanisms involved in GnRH-a action may lead to better therapeutic modalities for the treatment of advanced prostate cancer and other malignancies. (c) 2005 Elsevier Ireland Ltd. All rights reserved.