Pathophysiology of GTP-binding protein-linked receptors in hormone-sensitive tumors

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Synthetic agonists of GnRH have direct antiproliferative effects on certain hormone-sensitive tumors, including carcinoma of the endometrium, the ovary, the breast, and the prostate in vitro and in vivo. GnRH receptor has been demonstrated in the GnRH-sensitive tumors arising in reproductive organs, supporting the concept that GnRH receptor might mediate the direct antitumor effects of GnRH analog. We attempted to evaluate molecular relationship of its receptor to the growth-inhibiting activity, and obtained the following results.1) Activation of phosphotyrosine phosphatase by GnRH stimulated the loss of phosphotyrosine of endogenous proteins through GTP-binding protein within plasma membrane isolated from GnRH receptor-expressing tumors.2) Immunoblotting and ADP-ribosylation by bacterial toxins revealed the coupling of GnRH receptor to Gi protein subfamily. The Gi which couples GnRH receptor to the effector may define the difference of responses by peripheral tumor and the anterior pituitary.3) Fas, Fas ligand receptor, is frequently expressed in the GnRH receptor-positive tumors, but not in GnRH receptor-negative tumors.4) The apoptosis inducing Fas ligand appears in GnRH receptor-bearing tumors on GnRH stimulation through GnRH receptor-Gi system.Increased Fas ligand level within the GnRH receptor-bearing tumors might promote apoptotic cell death through attack on intratumoral Fas-positive cells that, could, at least in part, account for the antiproliferative action of the hormone.