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 (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 language	English
Pages (from-to)	1900-1916
Number of pages	17
Journal	Molecular Therapy
Volume	25
Issue number	8
Early online date	27 Apr 2017
DOIs	https://doi.org/10.1016/j.ymthe.2017.04.022
Publication status	Published - 2 Aug 2017

Keywords

Nrf2
Autophagy
innate antiviral response
IFN
Cancer
Oncolysis
VSV

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymthe.2017.04.022Licence: CC BY

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©2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 3.36 MBLicence: CC BY

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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

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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.",

keywords = "Nrf2, Autophagy, innate antiviral response, IFN, Cancer, Oncolysis, VSV",

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",

note = "Funding: Cancer Research UK (C20953/A18644) and the BBSRC (BB/L01923X/1).",

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doi = "10.1016/j.ymthe.2017.04.022",

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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

TY - JOUR

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.

KW - Nrf2

KW - Autophagy

KW - innate antiviral response

KW - IFN

KW - Cancer

KW - Oncolysis

KW - VSV

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U2 - 10.1016/j.ymthe.2017.04.022

DO - 10.1016/j.ymthe.2017.04.022

M3 - Article

C2 - 28527723

AN - SCOPUS:85020103515

SN - 1525-0016

VL - 25

SP - 1900

EP - 1916

JO - Molecular Therapy

JF - Molecular Therapy

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

Dinkova-Kostova, Albena

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

Abstract

Keywords

UN SDGs

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The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

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Dinkova-Kostova, Albena

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