MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.
MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.
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DOI：
10.1038/sj.bjc.6605180
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发表时间：
2009-07-21
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
X连锁的凋亡抑制蛋白(XIAP)是一种内源性的凋亡抑制蛋白，它可以决定上皮性卵巢癌(EOC)中caspase的积聚水平以及对顺铂等凋亡诱导剂的反应。此外，错配修复蛋白hMLH1通过p53依赖和非依赖机制与顺铂诱导的DNA损伤诱导的细胞凋亡有关。在这项研究中，hMLH1的表达与晚期(III-IV)卵巢癌患者对铂类药物的临床疗效和生存期相关。然后，我们研究了MLH1缺失是否是XIAP介导的顺铂抗凋亡反应的决定因素，并建立了具有不同P53状态的EOC细胞株。在MLH1熟练的细胞中，经历顺铂诱导的细胞杀伤的细胞百分比高于MLH1缺陷的细胞。此外，野生型hMLH1或hMLH1重新表达的存在显著增加了对MMR依赖的6-硫代鸟嘌呤的敏感性。对6-硫代鸟嘌呤和顺铂的细胞死亡反应与MLH1的显著蛋白分解、XIAP的不稳定和caspase-3活性的增加有关。SiRNA介导的XIAP抑制增加了MLH1熟练细胞的MLH1蛋白降解和细胞死亡，但不增加MLH1缺陷细胞的MLH1蛋白分解和细胞死亡。这些数据表明，XIAP抑制剂可能被证明是一种有效的手段，使EOC对MLH1依赖的细胞凋亡敏感。
The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III–IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.
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