Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells
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Gang Meng1, Mao Xia1, Diancheng Wang1, Aiping Chen1, Yongshan Wang4, Hongwei Wang1, Decai Yu1,2 and Jiwu Wei1,3
1 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
2 The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
3 Nanjing University Hightech Institute at Suzhou, Suzhou, China
4 Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
Jiwu Wei, email:
Decai Yu, email:
Keywords: Newcastle disease virus, mitophagy, apoptosis, autophagy, cancer
Received: May 29, 2014 Accepted: July 13, 2014 Published: July 15, 2014
Apoptosis contributes to antitumor effect of Newcastle disease virus (NDV). Autophagy is a protective response under cellular stress including viral infection. How autophagy interferes with oncolysis of NDV remains unclear. In this study, we found that NDV La Sota strain induced autophagy and preserved autophagic flux in non-small cell lung cancer cells. NDV-induced autophagy promoted viral replication by blocking cancer cells from caspase-dependent apoptosis. Moreover, we found that NDV recruited SQSTM1-mediated mitophagy to control cytochrome c release, and thus blocked intrinsic pro-apoptotic signaling. Finally, we observed an enhanced oncolysis in NSCLC cells treated with NDV in the presence of an autophagy inhibitor 3-methyladenine (3-MA). Interestingly, a more profound antitumor effect could be achieved when administration of 3-MA was postponed to 24 h after NDV infection. Our findings unveil a novel way that NDV subverts mitophagy to favor its replication by blocking apoptosis, and provide rationale for systemic therapeutic cohort combining NDV with autophagy inhibitors in cancer therapy.
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