Actions and mechanisms of action of gonadotrophin-releasing hormone (GNRH) in non-pituitary tissue
CA McArdle, CJ Caunt, KR Sedgley & AR Finch
Within the pituitary, GnRH acts via type I GnRH receptors to cause a Gq/11 mediated activation of PLC and consequent acute stimulation of gonadotrophin secretion and chronic regulation of gonadotrophin and GnRHR synthesis. The therapeutic effects of GnRH analogues are primarily (if not entirely) dependent upon activation, desensitisation or blockade of this system. There is also abundant evidence for expression of GnRHRs in extra-pituitary sites including the CNS, the immune system, various reproductive tissues and hormone-dependent cancers or cancer cell lines derived from such tissues. Since GnRH analogues can inhibit proliferation, stimulate apoptosis and slow invasion in various cancer models, there is immense interest in the possibility that the direct effects of GnRH analogues (or their cytotoxic derivatives) may also be exploited therapeutically. Using recombinant adenovirus to express type I GnRHRs in breast, prostate and endometrial cell lines, we find that they mediate a pronounced inhibition of proliferation and that their unique resistance to desensitisation may explain their efficacy in this regard. However, many aspects of GnRH analogue action in cancer cells remain controversial. Thus, although agonists are anti-proliferative and/or pro-apoptotic in some models, they can stimulate proliferation and/or inhibit apoptosis in others. Similarly, although GnRHRs appear to couple faithfully to Gq/11 and thereby stimulate MAPK in some cells, some effects on cancer cell proliferation may be mediated by Gi activation and consequent inhibition of MAPK signalling. In several models, peptides that act as antagonists at pituitary GnRHRs actually mimic effects of agonists, and GnRH-II can exert a potent anti-proliferative effect in spite of its low affinity for type I GnRHRs. Such data imply that functional characteristics of GnRHRs are dependent upon cell context and/or that GnRH effects on cancer cells are mediated by a distinct receptor (e.g. the type II human GnRHR). These possibilities will be discussed.