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.
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This work is supported by the Chinese NSFC.
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Jia-huan Lu and Zhi-feng Shi have contributed equally to this study.
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11010_2013_1922_MOESM1_ESM.eps
Figure S. Morphological change of A549 cells after Dox treatment with inhibitors or shRNA. Stable A549 cells expressing scramble shRNA, Cyp-D shRNA (clone-1 and clone-2) were either left untreated or stimulated with Dox (0.1 μM) for 72 h, cell morphology was taken. For the scramble shRNA transfected A549 cells, the effect of CsA (10 μM) and/or Z-VAD-fmk (ZVAD, 50 μM) on Dox-induced morphology change is also shown (*100) (EPS 6105 kb)
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Lu, Jh., Shi, Zf. & Xu, H. The mitochondrial cyclophilin D/p53 complexation mediates doxorubicin-induced non-apoptotic death of A549 lung cancer cells. Mol Cell Biochem 389, 17–24 (2014). https://doi.org/10.1007/s11010-013-1922-1
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DOI: https://doi.org/10.1007/s11010-013-1922-1