Department of Gastroenterology, East Hospital Affiliated to Tongji University in Shanghai, China.
Biochem Biophys Res Commun. 2013 Aug 9;437(4):526-31. doi: 10.1016/j.bbrc.2013.06.103. Epub 2013 Jul 8.
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.
胰腺癌仍然是大多数患者的致命疾病。顺铂对胰腺癌细胞显示出显著的细胞毒性作用，但潜在机制仍不明确。在这里，我们发现顺铂主要诱导胰腺癌细胞（AsPC-1 和 Capan-2）的非凋亡性死亡，这与明显的 p53 激活（磷酸化和积累）有关。进一步研究发现，激活的 p53 易位到线粒体，在那里与亲环蛋白 D（Cyp-D）形成复合物。我们提供了证据支持线粒体 Cyp-D/p53 复合物形成可能是顺铂诱导胰腺癌细胞非凋亡性死亡的关键。用其抑制剂环孢菌素 A（CsA）或 shRNA 介导的敲低抑制 Cyp-D 可抑制顺铂诱导的胰腺癌细胞死亡。CsA 和 Cyp-D 敲低均破坏了线粒体中 Cyp-D/p53 复合物的形成。同时，p53 敲低的胰腺癌细胞对顺铂产生抗性。另一方面，过表达 Cyp-D 的 HEK-293 对顺铂高度敏感。有趣的是，喜树碱（CMT）诱导的胰腺癌细胞凋亡死亡不受 CsA 或 Cyp-D 敲低的影响。总之，这些数据表明，顺铂诱导的非凋亡性死亡需要胰腺癌细胞中线粒体 Cyp-D-p53 信号通路。
