Activation of Nrf2 Signaling Augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

David Olagnier; 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; Rongtuan Lin

doi:10.1016/j.ymthe.2017.04.022

Activation of Nrf2 Signaling Augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

David Olagnier, 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, Rongtuan Lin

School of Medicine

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	1900-1916
Number of pages	17
Journal	Molecular Therapy
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.ymthe.2017.04.022
State	Published - Aug 2 2017

Keywords

autophagy
cancer
innate antiviral response
interferon
Nrf2
oncolysis
VSV

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1016/j.ymthe.2017.04.022

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Olagnier, D., Lababidi, R. R., Hadj, S. B., Sze, A., Liu, Y., Naidu, S. D., 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

Olagnier, D, Lababidi, RR, Hadj, SB, Sze, A, Liu, Y, Naidu, SD, Ferrari, M, Jiang, Y, Chiang, C, Beljanski, V, Goulet, ML, 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

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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 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.",

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AU - Lababidi, Rassin R.

AU - Hadj, Samar Bel

AU - Sze, Alexandre

AU - Liu, Yiliu

AU - Naidu, Sharadha Dayalan

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

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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 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.

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 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.

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Activation of Nrf2 Signaling Augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

Abstract

Keywords

ASJC Scopus subject areas

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