Olagnier David, Lababidi Rassin R, Hadj Samar Bel, Sze Alexandre, Liu Yiliu, Naidu Sharadha Dayalan, Ferrari Matteo, Jiang Yuan, Chiang Cindy, Beljanski Vladimir, Goulet Marie-Line, Knatko Elena V, Dinkova-Kostova Albena T, Hiscott John, Lin Rongtuan
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada; Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
Mol Ther. 2017 Aug 2;25(8):1900-1916. doi: 10.1016/j.ymthe.2017.04.022. Epub 2017 May 17.
Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the antioxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models. Chemoresistant A549 lung cancer cells that display constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulated viral replication in cancer cells and disrupted the type I IFN response via increased autophagy. This study reveals a previously unappreciated role for Nrf2 in the regulation of autophagy and the innate antiviral response that complements the therapeutic potential of VSV-directed oncolysis against multiple types of OV-resistant or chemoresistant cancer.
溶瘤病毒（OVs）为治疗多种类型的癌症提供了一种有前景的治疗方法。在本研究中，我们表明通过转录因子Nrf2对抗氧化网络进行调控可增强水疱性口炎病毒Δ51（VSVΔ51）的复制，并使癌细胞对病毒溶瘤作用敏感。抗氧化化合物萝卜硫素（SFN）激活Nrf2信号通路可导致VSVΔ51在对OV耐药的癌细胞中传播增强，并改善不同小鼠同基因和异种移植肿瘤模型中的治疗效果。显示Nrf2信号通路组成性显性高激活的化疗耐药A549肺癌细胞对VSVΔ51溶瘤作用尤为敏感。从机制上讲，增强的Nrf2信号通路刺激癌细胞中的病毒复制，并通过增加自噬破坏I型干扰素反应。本研究揭示了Nrf2在自噬调节和先天性抗病毒反应中以前未被认识的作用，这补充了VSV介导的溶瘤作用对多种OV耐药或化疗耐药癌症的治疗潜力。
