title: ABT737 reverses cisplatin resistance by regulating ER-mitochondria Ca2+ signal transduction in human ovarian cancer cells.
abstract: Bcl-2, which belongs to the Bcl-2 family, is frequently overexpressed in various types of cancer cells and contributes to drug resistance. However, the function of Bcl-2 in cisplatin resistance in human ovarian cancer cells is not fully understood. In this study, we found that the pharmacological inhibitor ABT737 or genetic knockdown of Bcl-2 increased cisplatin cytotoxicity in cisplatin-resistant ovarian cancer cells. Additionally, treatment with ABT737 or Bcl-2 siRNA increased cisplatin-induced free Ca2+ levels in the cytosol and mitochondria, which increased endoplasmic reticulum (ER)-associated and mitochondria-mediated apoptosis. In addition, ABT737 or Bcl-2 siRNA increased the ER-mitochondria contact sites induced by cisplatin in cisplatin-resistant SKOV3/DDP ovarian cancer cells. Consistently with the in vitro results, ABT737 potently synergized with cisplatin in inhibiting the growth of human ovarian cancer xenografts in nude mice. Collectively, these results indicate that pharmacological inhibitors or genetic knockdown of Bcl-2 may be a potential strategy for improving cisplatin treatment of ovarian cancer.
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: School of Public Health, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Bingxuan
authors.initials: B
authors.lastname: Jiao
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Luyan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, The China-Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China.
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Pathology, Basic Medical College, Beihua University, Jilin, Jilin 132013, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xianrui
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Histology and Embryology, Basic College of Medicine, Jilin Medical University, Jilin, Jilin 132013, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D064593:Heterografts / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009596:Nitrophenols / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D002945:Cisplatin; D002118:Calcium