[Recent data on GnRH receptors].
The main intracellular pathway activated by stimulation of GnRH receptors is related to Gq protein which induces a cytoplasmic metabolic cascade responsible for activation of genes producing gonadotrophins and regulating their secretion. Two other activation pathways were identified, a Gs protein-mediated pathway involved in pulsatile secretion of GnRH and a Gi protein-mediated pathway with an inhibitory and apototic effect on tumor cells. Finally, GnRH receptors may directly interact with membrane integrins and generate other cytoplasmic signals. Hence, GnRH receptors are not only involved in pituitary secretion but also in tumoral disease. The inhibitory effect of GnRH analogs on the secretion of sex steroids is responsible for the indirect anti-tumoral action already used in routine practice for the treatment of hormone-dependent cancer. However, the presence of GnRH receptors in tumor tissues suggests that they are directly involved in cancerous disease. The conformational variability of these receptors permits certain ligands to stabilize them in a form privileging various intracellular signals with activation of metabolic pathways involving protein kinase systems and generating a direct antitumoral effect by inhibition of cell growth and\or apotosis. The absence of an intracytoplasmic C-terminal tail in the structure of these receptors is an essential condition for the anti-proliferative effect of various ligands, agonists or antagonists, with an anti-tumoral activity varying according to their specificity. This will make it possible in the future to establish a new classification of GnRH analogs. The discovery of this direct antitumoral effect has therefore opened up a new therapeutic approach for hormone-independant cancers with GnRH receptors and the direct cytotoxic effect reinforces the hormonal action in hormone-dependant cancers.
Millar
Robert
R
Medical Research Council, Human Reproductive Sciences Unit, Edimburgh, Royaume-Uni.
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000502:physiology; D006062:Gonadotropins / Q000378:metabolism; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D011966:Receptors, LHRH / Q000502:physiology*
D000970:Antineoplastic Agents; D006062:Gonadotropins; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D011494:Protein Kinases