GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-induced MAPKs p38 and JNK and Proapoptotic Protein Bax
GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-induced MAPKs p38 and JNK and Proapoptotic Protein Bax
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DOI：
10.1158/0008-5472.can-08-4657
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Gruendker, Carsten
中科院分区：
文献类型：
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作者：
Fister, Stefanie;Guenthert, Andreas R.;Gruendker, Carsten
最近，我们发现促性腺激素释放激素 (GnRH)-II 拮抗剂在体外和体内诱导人子宫内膜、卵巢和乳腺癌细胞凋亡。在本研究中，我们确定了 GnRH-II 拮抗剂的受体结合以及对促有丝分裂信号转导和促凋亡蛋白 Bax 激活的影响。测试的 GnRH-II 拮抗剂显示 GnRH-I 受体结合的 EC50 值在 1 至 2 nmol/L 范围内。 GnRH-II 激动剂 [D-Lys(6)]GnRH-II 显示与 GnRH-I 受体结合的 EC50 值类似于 1,000 nmol/L。 [D-Lys(6)]GnRH-II 对 GnRH-I 受体功能具有激动活性，EC50 为 13 nmol/L。 GnRH-II 拮抗剂的拮抗活性测定结果为 EC50 值在 1 nmol/L 范围内。用 GnRH-II 拮抗剂处理人子宫内膜、卵巢和乳腺癌细胞导致应激诱导的丝裂原激活蛋白激酶 p38 和 c-Jun NH2 末端激酶的时间依赖性激活。此外，GnRH-II 拮抗剂治疗可诱导促凋亡蛋白 Bax 的时间依赖性激活。 GnRH-II 拮抗剂不参与蛋白激酶 B/Akt 或细胞外信号调节激酶 1/2 的激活。测试的GnRH-II拮抗剂与GnRH-I受体具有与GnRH-I拮抗剂西曲瑞克相似的结合亲和力。参考环AMP反应元件报告基因激活测定，GnRH-II激动剂[D-Lys(6)]GnRE-II必须被归类为GnRH-I受体的激动剂，而测试的GnRH-II拮抗剂是GnRH-I受体的明显拮抗剂。 GnRH-II 拮抗剂通过激活应激诱导的丝裂原激活蛋白激酶 p38 和 c-Jun NH2 末端激酶，然后激活促凋亡蛋白 Bax，诱导人子宫内膜、卵巢和乳腺癌细胞凋亡。 [癌症研究 2009;69(16):6473-81]
Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [D-Lys(6)]GnRH-II showed an EC50 value for GnRH-I receptor binding of similar to 1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC50 of 13 nmol/L has been determined for [D-Lys(6)]GnRH-II. Antagonistic activities with EC50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist [D-Lys(6)]GnRE-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase followed by activation of proapoptotic protein Bax. [Cancer Res 2009;69(16):6473-81]