Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

David Olagnier (Lead / Corresponding author), Rassin R. Lababidi, Samar Bel Hadj, Alexandre Sze, Yiliu Liu, Sharadha Dayalan Naidu, Matteo Ferrari, Yuan Jiang, Cindy Chiang, Vladimir Beljanski, Marie-Line Goulet, Elena V. Knatko, Albena T. Dinkova-Kostova, John Hiscott (Lead / Corresponding author), Rongtuan Lin (Lead / Corresponding author)

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    Abstract

    Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the anti-oxidant 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. Furthermore, chemoresistant A549 lung cancer cells that display a constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulates viral replication in cancer cells and disrupts 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.
    Original languageEnglish
    Pages (from-to)1900-1916
    Number of pages17
    JournalMolecular Therapy
    Volume25
    Issue number8
    Early online date27 Apr 2017
    DOIs
    Publication statusPublished - 2 Aug 2017

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    Keywords

    • Nrf2
    • Autophagy
    • innate antiviral response
    • IFN
    • Cancer
    • Oncolysis
    • VSV

    Cite this

    Olagnier, D., Lababidi, R. R., Bel Hadj, S., Sze, A., Liu, Y., Dayalan Naidu, S., Ferrari, M., Jiang, Y., Chiang, C., Beljanski, V., Goulet, M-L., Knatko, E. V., Dinkova-Kostova, A. T., Hiscott, J., & Lin, R. (2017). Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity. Molecular Therapy, 25(8), 1900-1916. https://doi.org/10.1016/j.ymthe.2017.04.022