title: PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China. yuanzhang75@hotmail.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000150:complications; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000150:complications; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000032:analysis / Q000502:physiology*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000150:complications; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D002945:Cisplatin
keywords: Akt; Cisplatin resistant; EOC; Epithelial ovarian cancer; MMR; Mismatch repair; PMS2; Postmeiotic segregation increased 2; Protein kinase B