GnRH receptor and apoptotic signaling.

In addition to its hypophysiotropic action, gonadotropin-releasing hormone (GnRH) can modify activity in extrapituitary organs and peripheral tumors. GnRH analogs are the preferred treatment for advanced and even metastatic or recurring carcinomas in vivo and in vitro. Hormone-responsive tumors undergo apoptosis with the appropriate stimulus; GnRH-induced tumor growth arrest may result from stimulated apoptotic cell death. The sensitivity of tumors and normal tissue to GnRH is strongly associated with the possession of receptors for GnRH as well as other hormonal control. Despite the lack of a precise apoptotic signaling cascade through GnRH receptors, biochemical events observed within a plasma membrane appear to constitute the most convincing evidence that the membrane event is primarily stimulated during cell activation by GnRH. GnRH receptors in tumors differ from those in pituitary gonadotrophs in some aspects, in particular with regard to the transmembrane signaling cascade. The intramembranous phenomena that occur independently of the contribution of other organelles upon tumoral GnRH receptor engagement include (i) activation of phosphotyrosine phosphatase and loss of phosphotyrosine from the endogenous membrane protein and (ii) phosphoinositide and perhaps sphingomyelin cleavage producing lipid-originated second messengers. GnRH has also been demonstrated to increase Fas ligand expression within plasma membrane, which is known to promote apoptotic cell death through attack on Fas-positive cells within tumors. The Fas-Fas ligand complex might, at least in part, account for the antiproliferative action of the hormone. An understanding of the relationship between the extracellular (hormonal) stimuli that leads to cell death and the intracellular events regulating growth arrest on GnRH action may fundamentally help clarify the therapeutic approach to all hormone-dependent carcinomas that respond to stimuli that lead to apoptosis. In this chapter, we review the recent literature and the results of our studies on GnRH-induced membrane events and summarize what is currently known about this promising antiproliferative function.