title: The mitochondrial cyclophilin D/p53 complexation mediates doxorubicin-induced non-apoptotic death of A549 lung cancer cells.
abstract: Doxorubicin has displayed significant cytotoxic effects against the lung cancer cells; however, the underlying mechanisms remain inconclusive. In the current study, we provided evidence to show that mitochondrial p53 and cyclophilin D (Cyp-D) complexation is required for doxorubicin-induced death of lung cancer A549 cells. Doxorubicin induced both apoptotic and non-apoptotic death of A549 cells. Cyclosporine A (CsA), the Cyp-D inhibitor, and Cyp-D silencing were prevented doxorubicin-induced non-apoptotic death of A549 cells, while cells overexpressing Cyp-D were hyper-sensitive to doxorubicin. In A549 cells, doxorubicin-activated p53, the latter translocated to mitochondria and physically interacted with Cyp-D. The p53/Cyp-D mitochondrial complexation was prevented by CsA or Cyp-D silencing, or by p53 inhibitor pifithrin-α. Significantly, doxorubicin-induced anti-tumor ability in vivo was also compromised by CsA, or when Cyp-D was silenced. Together, these data suggested that Dox-induced non-apoptotic death of A549 cells requires mitochondrial Cyp-D-p53 complexation.
authors.affiliation: Department of Internal Medicine, Shanghai Changning Center Hospital, No. 1111, Xianxia Road, Changning District, Shanghai, 200336, China.
authors.forename: Jia-Huan
authors.initials: JH
authors.lastname: Lu
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Shi
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D004317:Doxorubicin; D016572:Cyclosporine; C121565:pifithrin; D021983:Cyclophilins