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

激素敏感肿瘤中 GTP 结合蛋白相关受体的病理生理学

基本信息

批准号：
07457383
负责人：
IMAI Atsushi
金额：
$ 2.94万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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.

GnRH的合成激动剂在体内外对某些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受体在发生于生殖器官的GnRH敏感肿瘤中已被证实，支持GnRH受体可能介导GnRH类似物的直接抗肿瘤作用的概念。我们试图评估其受体与生长抑制活性的分子关系，得到以下结果：1)GnRH激活磷酸酪氨酸磷酸酶，通过GnRH受体表达的肿瘤细胞质膜上的GTP结合蛋白，刺激内源性蛋白的磷酸酪氨酸丢失。2)细菌毒素的免疫印迹和ADP核糖化表明GnRH受体与Gi蛋白亚家族偶联。3)Fas、Fas配体受体在GnRH受体阳性的肿瘤中经常表达，而在GnRH受体阴性的肿瘤中不表达。4)在GnRH受体-GI系统的刺激下，GnRH受体阳性的肿瘤中出现了凋亡诱导的Fas配体。携带GnRH受体的肿瘤内Fas配体水平的增加可能通过攻击瘤内Fas阳性细胞而促进细胞死亡，这至少部分可能是激素的抗增殖作用。