Department of Internal Medicine, Shanghai Changning Center Hospital, No. 1111, Xianxia Road, Changning District, Shanghai, 200336, China.
Mol Cell Biochem. 2014 Apr;389(1-2):17-24. doi: 10.1007/s11010-013-1922-1. Epub 2013 Dec 17.
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.
多柔比星对肺癌细胞表现出显著的细胞毒性作用；然而，其潜在机制尚不清楚。在本研究中，我们提供的证据表明，线粒体 p53 和亲环素 D（Cyp-D）复合物的形成是多柔比星诱导肺癌 A549 细胞死亡所必需的。多柔比星诱导 A549 细胞发生凋亡和非凋亡性死亡。环孢素 A（CsA），Cyp-D 抑制剂，以及 Cyp-D 沉默可预防多柔比星诱导的 A549 细胞非凋亡性死亡，而过表达 Cyp-D 的细胞对多柔比星更为敏感。在 A549 细胞中，多柔比星激活 p53，后者易位到线粒体并与 Cyp-D 发生物理相互作用。CsA 或 Cyp-D 沉默，或 p53 抑制剂 pifithrin-α均可阻止 p53/Cyp-D 线粒体复合物的形成。重要的是，CsA 或 Cyp-D 沉默也会损害多柔比星在体内的抗肿瘤能力。总之，这些数据表明 Dox 诱导的 A549 细胞非凋亡性死亡需要线粒体 Cyp-D-p53 复合物的形成。
