Xia Mao, Meng Gang, Jiang Aiqin, Chen Aiping, Dahlhaus Meike, Gonzalez Patrick, Beltinger Christian, Wei Jiwu
Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Nanjing University Hightech Institute at Suzhou, Suzhou, China.
Oncotarget. 2014 Jun 15;5(11):3907-18. doi: 10.18632/oncotarget.2028.
Although apoptotic phenomena have been observed in malignant cells infected by measles virus vaccine strain Edmonston B (MV-Edm), the precise oncolytic mechanisms are poorly defined. In this study we found that MV-Edm induced autophagy and sequestosome 1-mediated mitophagy leading to decreased cytochrome c release, which blocked the pro-apoptotic cascade in non-small cell lung cancer cells (NSCLCs). The decrease of apoptosis by mitophagy favored viral replication. Persistent viral replication sustained by autophagy ultimately resulted in necrotic cell death due to ATP depletion. Importantly, when autophagy was impaired in NSCLCs MV-Edm-induced cell death was significantly abrogated despite of increased apoptosis. Taken together, our results define a novel oncolytic mechanism by which mitophagy switches cell death from apoptosis to more efficient necrosis in NSCLCs following MV-Edm infection. This provides a foundation for future improvement of oncolytic virotherapy or antiviral therapy.
尽管在感染麻疹病毒疫苗株埃德蒙斯顿B（MV-Edm）的恶性细胞中已观察到凋亡现象，但确切的溶瘤机制尚不清楚。在本研究中，我们发现MV-Edm诱导自噬和隔离小体1介导的线粒体自噬，导致细胞色素c释放减少，从而阻断了非小细胞肺癌细胞（NSCLC）中的促凋亡级联反应。线粒体自噬导致的凋亡减少有利于病毒复制。由自噬维持的持续病毒复制最终由于ATP耗竭导致坏死性细胞死亡。重要的是，当NSCLC中的自噬受损时，尽管凋亡增加，MV-Edm诱导的细胞死亡仍显著消除。综上所述，我们的结果定义了一种新的溶瘤机制，即线粒体自噬在MV-Edm感染后将NSCLC中的细胞死亡从凋亡转变为更有效的坏死。这为未来溶瘤病毒疗法或抗病毒疗法的改进奠定了基础。
