Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells.

Ke Jiang,Guirong Zhang,Jiansheng Xu,Yingchun Li,Qiumin Zhu,Yupeng Wang,Wuguo Deng,Quentin Liu,Songshu Meng

doi:10.1186/1471-2407-14-551

Abstract

BackgroundOncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells.MethodsThe effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells.ResultsWe show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively.ConclusionsThese results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.

Highlights

Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance
In addition to targeting the cellular apoptosis machinery, we recently reported that oncolytic Newcastle disease virus (NDV) induces autophagy in U251 human glioma cells to promote virus production [17], suggesting that autophagy may be involved in NDVinduced oncolysis
We previously reported that oncolytic NDV induces apoptosis in cisplatin-resistant A549 (A549/DDP) and parental cells [4,8]

Summary

Introduction

Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance. Oncolytic viruses (OVs) are emerging as new cancer therapeutic approaches with over-expressing Bcl-xL, a known anti-apoptotic protein [13] These studies and studies from our lab indicate a potential role of oncolytic NDV in the treatment of drugresistant lung cancers. Since OV infections can interact with the cellular autophagy machinery, OV in combination with an autophagy modulator would enhance the antitumor immune responses, thereby improving OV-mediated efficacy [29,30,31]. Together, data from these studies strongly indicate that targeting autophagy may be utilized as a novel strategy for enhancing the oncolytic virotherapy of cancers

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