title: p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers.
abstract: Mitochondria are highly dynamic organelles, and mitochondrial fission is a crucial step of apoptosis. Although Oma1 is believed to be responsible for long form Opa1 (L-Opa1) processing during mitochondrial fragmentation, whether and how Oma1 is involved in L-Opa1 processing and participates in the regulation of chemoresistance is unknown. Chemosensitive and chemoresistant ovarian (OVCA) and cervical (CECA) cancer cells were treated with cisplatin (CDDP). Mitochondrial dynamics and protein contents were assessed by immunofluorescence and Western blot, respectively. The requirements of Oma1 and p53 for CDDP-induced L-Opa1 processing, mitochondrial fragmentation, and apoptosis were examined by siRNA or cDNA. CDDP induces L-Opa1 processing and mitochondrial fragmentation in chemosensitive but not in chemoresistant cells. CDDP induced Oma1 40-kDa form increases in OV2008 cells, not in C13* cells. Oma1 knockdown inhibited L-Opa1 processing, mitochondrial fragmentation, and apoptosis. Silencing p53 expression attenuated the effects of CDDP in Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis in chemosensitive OVCA cells, whereas reconstitution of p53 in p53 mutant or null chemoresistant OVCA cells induced Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis irrespective of the presence of CDDP. Prohibitin 1 (Phb1) dissociates from Opa1-Phb1 complex and binds phosphorylated p53 (serine 15) in response to CDDP in chemosensitive but not chemoresistant CECA cells. These findings demonstrate that (a) p53 and Oma1 mediate L-Opa1 processing, (b) mitochondrial fragmentation is involved in CDDP-induced apoptosis in OVCA and CECA cells, and (c) dysregulated mitochondrial dynamics may in part be involved in the pathophysiology of CDDP resistance.
authors.affiliation: Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada, and.
authors.forename: Bao
authors.initials: B
authors.lastname: Kong
authors.affiliation: Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada, and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada, and.
authors.forename: Ella
authors.initials: E
authors.lastname: Fung
authors.affiliation: Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada, and; State Key Laboratory of Reproductive Medicine, Clinical Reproductive Medicine Centre, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xue
authors.affiliation: Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada, and. Electronic address: btsang@ohri.ca.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D010051:Ovarian Neoplasms / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000091402:Prohibitins; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008666:Metalloendopeptidases; C477817:molecule metalloprotease-related protein-1, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D002945:Cisplatin
keywords: Apoptosis; CDDP; Chemoresistance; Mitochondrial Fragmentation; Oma1; Opa1; Ovarian Cancer; Protein-Protein Interaction; p53
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