title: Cisplatin-induced necroptosis in TNFα dependent and independent pathways.
abstract: Cisplatin is a chemotherapeutic drug for treatment of many solid tumors. It has been shown to induce apoptosis and/or necrosis in different types of cancer cells. However, the underlying mechanisms remain elusive. In this study, we provide evidences that cisplatin induces necroptosis in receptor-interacting protein 3 (RIP3)-expressing cell lines, but not in cell lines lacking RIP3 protein expression. Deficiency of core components of necroptotic pathway, RIP1, RIP3, or mixed lineage kinase domain-like protein (MLKL) blocked cisplatin-induced cell death in L929 cells. This phenomenon is dependent on RIP1/RIP3/MLKL necrosome formation and translocation to mitochondria-associated membrane (MAM), but only partially via autocrine production of tumor necrosis factor α (TNFα). Moreover, we demonstrate that the mitochondrial permeability transition pore opening (mPTP) opening and reactive oxygen species (ROS) generation is a critical downstream event of the formation of necrosome in cisplatin-induced necroptosis, which is TNFα independent. Deficiency of cyclophilin-D (CypD) partially reduced cisplatin-induced cell death, indicating CypD mediated-mPTP opening plays an important role during cisplatin-induced necroptosis. Both deletion of CypD and TNFα completely blocked cisplatin-induced cell death, suggesting that cisplatin could induce necroptosis through TNFα dependent and independent pathway. These findings provide new insight into the molecular mechanisms underlying cisplatin-induced necroptosis.
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. Electronic address: xuyanfang99@hotmail.com.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Hua-Bin
authors.initials: HB
authors.lastname: Ma
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
authors.forename: Yu-Lu
authors.initials: YL
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
authors.forename: Rui-Qing
authors.initials: RQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D009336:Necrosis; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C570694:MLKL protein, mouse; D011494:Protein Kinases; D021983:Cyclophilins; D002945:Cisplatin