PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis
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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.
KeywordsEOC Epithelial ovarian cancer PMS2 Postmeiotic segregation increased 2 MMR Mismatch repair Akt Protein kinase B Cisplatin resistant
Our research was supported by the National Natural Science Foundation of China (Nos. 81072133, 81302265, and 81272860) and Wuhan Science and Technology Bureau (No. 2014060101010042).
Conflicts of interest
All the authors declare no conflicts of interest.
- 16.Ali AY, Kim JY, Pelletier JF, Vanderhyden BC, Bachvarov DR, Tsang BK. Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability. Mol Carcinog 2014Google Scholar