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

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

73 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
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

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

Funding

The authors thank Alexander Ivanov, Josie Ursini-Siegel, Hyman Schipper, Volker Blank, and Mark Wainberg for reagents used in this study. This research work was supported by a Canadian Institutes of Health Research grant (MOP130401) and a Prostate Cancer Research Foundation of Canada grant (D2013-23) to R.L. and J.H., grants from Fondazione Cenci Bolognetti, the NIH (1R21CA192185- 01) and the Italian Association for Cancer Research (AIRC-AG16901) to J.H., and grants from Cancer Research UK (C20953/A18644) and the BBSRC (BB/L01923X/1) to A.T.D.-K. D.O. was supported by a Peter Quinlan McGill Postdoctoral Fellowship and a Canadian Cancer Society Travel Award grant. A.S. was supported by a Fond de la Recherche Sante Quebec (FRSQ) Fellowship award. The authors declare that the data supporting the findings of this study are available within the paper and can be made available from the corresponding authors upon reasonable request.

Funders	Funder number
Canadian Institutes of Health Research	MOP130401
Prostate Cancer Research Foundation of Canada	D2013-23
National Institutes of Health	1R21CA192185- 01
Italian Association for Cancer Research	AIRC-AG16901
Cancer Research UK	C20953/A18644
???publication-publication-funding-organisation-not-added???	BB/L01923X/1

ASJC Scopus Subject Areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

Keywords

autophagy
cancer
innate antiviral response
interferon
Nrf2
oncolysis
VSV

Disciplines

Medical Molecular Biology
Genetics
Pharmacology

Access to Document

10.1016/j.ymthe.2017.04.022

Cite this

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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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

Bibliographical note

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

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