PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis
PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis
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上皮性卵巢癌中 PMS2 的表达受 Akt 翻译后调节，对于铂诱导的细胞凋亡至关重要
DOI：
10.1007/s13277-015-4143-2
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Zhang, Yuan
中科院分区：
文献类型：
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作者：
Jia, Jinghui;Wang, Zehua;Zhang, Yuan
上皮性卵巢癌(EOC)是妇科恶性肿瘤中致死率最高的肿瘤，主要是由于顺铂耐药的晚期诊断和发展所致。肿瘤细胞对顺铂的敏感性经常受到DNA错配修复缺陷的影响，错配修复修复错配的DNA序列并调节DNA损伤诱导的细胞凋亡。然而，MMR蛋白家族成员减数分裂后分离增加2(PMS2)在顺铂耐药中的作用仍不清楚。在本研究中，我们发现在EOC细胞系和组织中经常存在PMS2的缺失和Akt的磷酸化。复合免疫沉淀(co-IP)和蛋白质稳定性分析结果表明，活化的Akt能直接与PMS2结合，并在EOC细胞中引起PMS2的降解。此外，功能实验表明，PMS2是顺铂诱导细胞凋亡和细胞周期停滞于G2/M期所必需的。这些发现为MMR与化疗耐药之间的分子机制提供了新的见解，并提示稳定PMS2表达可能有助于克服上皮性卵巢癌顺铂耐药。
Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, mainly due to the advanced stage at diagnosis and development of cisplatin resistance. The sensitivity of tumor cells to cisplatin is frequently affected by defect in DNA mismatch repair (MMR), which repairs mispaired DNA sequences and regulates DNA-damage-induced apoptosis. However, the role of postmeiotic segregation increased 2 (PMS2), a member of MMR protein family, in cisplatin resistance remains elusive. In the present study, we demonstrated the frequent deficiency of PMS2 and phosphorylation of Akt in EOC cell lines and tissues. Results of complex immunoprecipitation (co-IP) and protein stability assay indicated that activated Akt could directly bind to PMS2 and cause degradation of PMS2 in EOC cells. In addition, functional experiments revealed that PMS2 was required for cisplatin-induced apoptosis and cell cycle arrest in G2/M phase. These findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC.