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

GnRH的合成激动剂在体外和体内对某些对激素敏感的肿瘤具有直接的抗增殖作用，包括子宫内膜癌、卵巢癌、乳腺癌和前列腺癌。GnRH受体在生殖器官的GnRH敏感性肿瘤中已被证实，支持GnRH受体可能介导GnRH类似物的直接抗肿瘤作用的概念。结果表明：（1）GnRH激活磷酸酪氨酸磷酸酶后，可通过细胞膜上的GTP结合蛋白，促进内源性蛋白磷酸酪氨酸的丢失;（2）免疫印迹和细菌毒素ADP-核糖基化反应显示GnRH受体与Gi蛋白亚家族偶联。GnRH受体与垂体前叶细胞的Gi偶联可能决定了外周型肿瘤和垂体前叶细胞的反应差异。3）Fas是Fas配体受体，在GnRH受体阳性的肿瘤中表达频繁，而在GnRH受体阴性的肿瘤中不存在。4）在GnRH刺激下，GnRH受体阳性的肿瘤中出现凋亡诱导Fas配体，其作用是通过GnRH受体介导的。携带GnRH受体的肿瘤内Fas配体水平的增加可能通过攻击肿瘤内Fas阳性细胞而促进凋亡性细胞死亡，这至少可以部分地解释激素的抗增殖作用。

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.