Jia Jinghui, Wang Zehua, Cai Jing, Zhang Yuan
Department of Obstetrics and Gynecology, Air Force General Hospital, PLA, Beijing, 100142, People's Republic of China.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
Tumour Biol. 2016 Mar;37(3):3059-69. doi: 10.1007/s13277-015-4143-2. Epub 2015 Sep 30.
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.
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤，主要原因是诊断时已处于晚期且出现顺铂耐药。肿瘤细胞对顺铂的敏感性常受DNA错配修复（MMR）缺陷的影响，MMR可修复错配的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，我们证明了EOC细胞系和组织中PMS2频繁缺失以及Akt磷酸化。免疫共沉淀（co-IP）和蛋白质稳定性分析结果表明，活化的Akt可直接与PMS2结合并导致EOC细胞中PMS2降解。此外，功能实验表明，顺铂诱导的细胞凋亡和G2/M期细胞周期阻滞需要PMS2。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，并表明稳定PMS2表达可能有助于克服EOC中的顺铂耐药。
