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

    Fingerprint

    Vesicular Stomatitis
    Autophagy
    Antiviral Agents
    Immunity
    Oncolytic Viruses
    Viruses
    Neoplasms
    Virus Replication
    Heterografts
    Oxidants
    Lung Neoplasms
    Transcription Factors
    Therapeutics
    Antioxidants

    Keywords

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

    Cite this

    Olagnier, David ; Lababidi, Rassin R. ; Bel Hadj, Samar ; Sze, Alexandre ; Liu, Yiliu ; Dayalan Naidu, Sharadha ; Ferrari, Matteo ; Jiang, Yuan ; Chiang, Cindy ; Beljanski, Vladimir ; Goulet, Marie-Line ; Knatko, Elena V. ; Dinkova-Kostova, Albena T. ; Hiscott, John ; Lin, Rongtuan. / Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity. In: Molecular Therapy. 2017 ; Vol. 25, No. 8. pp. 1900-1916.
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    title = "Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity",
    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.",
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    author = "David Olagnier and Lababidi, {Rassin R.} and {Bel Hadj}, Samar and Alexandre Sze and Yiliu Liu and {Dayalan Naidu}, Sharadha and Matteo Ferrari and Yuan Jiang and Cindy Chiang and Vladimir Beljanski and Marie-Line Goulet and Knatko, {Elena V.} and Dinkova-Kostova, {Albena T.} and John Hiscott and Rongtuan Lin",
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    Olagnier, D, Lababidi, RR, Bel Hadj, S, Sze, A, Liu, Y, Dayalan Naidu, S, Ferrari, M, Jiang, Y, Chiang, C, Beljanski, V, Goulet, M-L, Knatko, EV, Dinkova-Kostova, AT, Hiscott, J & Lin, R 2017, 'Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity', Molecular Therapy, vol. 25, no. 8, pp. 1900-1916. https://doi.org/10.1016/j.ymthe.2017.04.022

    Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity. / Olagnier, David (Lead / Corresponding author); Lababidi, Rassin R.; Bel Hadj, Samar; Sze, Alexandre; Liu, Yiliu; Dayalan Naidu, Sharadha; Ferrari, Matteo; Jiang, Yuan; Chiang, Cindy; Beljanski, Vladimir; Goulet, Marie-Line; Knatko, Elena V.; Dinkova-Kostova, Albena T.; Hiscott, John (Lead / Corresponding author); Lin, Rongtuan (Lead / Corresponding author).

    In: Molecular Therapy, Vol. 25, No. 8, 02.08.2017, p. 1900-1916.

    Research output: Contribution to journalArticle

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    T1 - Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

    AU - Olagnier, David

    AU - Lababidi, Rassin R.

    AU - Bel Hadj, Samar

    AU - Sze, Alexandre

    AU - Liu, Yiliu

    AU - Dayalan Naidu, Sharadha

    AU - Ferrari, Matteo

    AU - Jiang, Yuan

    AU - Chiang, Cindy

    AU - Beljanski, Vladimir

    AU - Goulet, Marie-Line

    AU - Knatko, Elena V.

    AU - Dinkova-Kostova, Albena T.

    AU - Hiscott, John

    AU - Lin, Rongtuan

    N1 - Funding: Cancer Research UK (C20953/A18644) and the BBSRC (BB/L01923X/1).

    PY - 2017/8/2

    Y1 - 2017/8/2

    N2 - 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.

    AB - 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.

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    KW - innate antiviral response

    KW - IFN

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