Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells.

Gang Meng,Decai Yu,Jiwu Wei,Hongwei Wang,Yongshan Wang,Diancheng Wang,Mao Xia,Aiping Chen

doi:10.18632/oncotarget.2219

Gang Meng, Decai Yu + Show 6 more

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https://doi.org/10.18632/oncotarget.2219

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Abstract

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.

Highlights

Understanding oncolytic mechanisms in cancer cells is crucial for further improvement of oncolytic virotherapy
Lipidation of LC3 was not induced by heat-inactivated Newcastle disease virus (NDV) (Fig. 1D), suggesting that active viral replication is required for autophagy induction
Our study characterizes for the first time that oncolytic NDV La Sota strain usurps SQSTM1-mediated mitophagy to promote viral replication by mitigating intrinsic pro-apoptotic cascades initiated by cytochrome c release

Summary

Introduction

Understanding oncolytic mechanisms in cancer cells is crucial for further improvement of oncolytic virotherapy. Studies show that apoptosis dominantly contributes to NDVinduced cell death [3, 4]. Both extrinsic and intrinsic apoptotic pathways can be activated in cancer cells after infection with NDV including Beaudette C and La Sota strains [4]. Several previous studies have demonstrated that the preferential antitumor activity of NDV is not due to impaired antiviral innate immune responses in tumor cells, in which robust type I IFN responses have been observed after viral infection [7,8,9]. Some recent reports show that the oncolytic NDV preferentially replicates in apoptosisresistant cells overexpressing Bcl-XL or Livin, and exerts a more profound antitumor effect [6, 10]

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