title: Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling.
abstract: The pancreatic cancer remains a fatal disease for the majority of patients. Cisplatin has displayed significant cytotoxic effects against the pancreatic cancer cells, however the underlying mechanisms remain inconclusive. Here, we found that cisplatin mainly induced non-apoptotic death of the pancreatic cancer cells (AsPC-1 and Capan-2), which was associated with a significant p53 activation (phosphorylation and accumulation). Further, activated p53 was found to translocate to mitochondria where it formed a complex with cyclophilin D (Cyp-D). We provided evidences to support that mitochondrial Cyp-D/p53 complexation might be critical for cisplatin-induced non-apoptotic death of pancreatic cancer cells. Inhibition of Cyp-D by its inhibitor cyclosporine A (CsA), or by shRNA-mediated knockdown suppressed cisplatin-induced pancreatic cancer cell death. Both CsA and Cyp-D knockdown also disrupted the Cyp-D/p53 complex formation in mitochondria. Meanwhile, the pancreatic cancer cells with p53 knockdown were resistant to cisplatin. On the other hand, HEK-293 over-expressing Cyp-D were hyper-sensitive to cisplatin. Interestingly, camptothecin (CMT)-induced pancreatic cancer cell apoptotic death was not affected CsA or Cyp-D knockdown. Together, these data suggested that cisplatin-induced non-apoptotic death requires mitochondria Cyp-D-p53 signaling in pancreatic cancer cells.
authors.affiliation: Department of Gastroenterology, East Hospital Affiliated to Tongji University in Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing-xu
authors.initials: JX
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.forename: Gao-jue
authors.initials: GJ
authors.lastname: Wu
authors.forename: Tu
authors.initials: T
authors.lastname: Dai
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D021983:Cyclophilins; D002945:Cisplatin
keywords: 3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium bromide; CMT; CsA; Cyclophilin-D; Cyp-D; MTT; Mitochondrion and cell death; Pancreatic cancer; camptothecin; cyclophilin D; cyclosporine A; mPTP; mitochondrial permeability transition pore; p53