title: Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis.
abstract: The mechanism of cisplatin resistance in ovarian cancer is not fully understood. In the present study, we showed a critical role for endoplasmic reticulum (ER) stress tolerance in mediating cisplatin resistance in human ovarian cancer cells. We found cisplatin to inhibit the proliferation of two ovarian cancer cell lines: cisplatin-sensitive SKOV3 cells and cisplatin‑resistant SKOV3/DDP cells. However, the effect was greater in the cisplatin-sensitive SKOV3 cells. Cisplatin treatment induced ER stress in the SKOV3 cells but not in the SKOV3/DDP cells. Cisplatin-induced Ca2+ flow from the ER into mitochondria caused mitochondrial calcium overload, which amplified proapoptotic signaling in the cisplatin-sensitive SKOV3 cells. ER stress-mediated apoptosis and mitochondrial pathway-dependent apoptosis were induced in the cisplatin-sensitive SKOV3 cells, but not in the cisplatin-resistant SKOV3/DDP cells. Moreover, there were more ER-mitochondria contacts in the cisplatin-treated SKOV3 cells. Collectively, our data indicated that tolerance to cisplatin-induced ER stress inhibits ER stress-mediated apoptosis, prevents an imbalance in ER and mitochondrial calcium homeostasis and maintains cell survival, thus leading to cisplatin resistance in ovarian cancer cells.
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Linchuan
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Shibing
authors.initials: S
authors.lastname: Liu
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, Jilin Medical University, Jilin City, Jilin 132013, P.R. China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D002945:Cisplatin; D002118:Calcium