Format

Send to

Choose Destination
Mol Ther. 2017 Aug 2;25(8):1900-1916. doi: 10.1016/j.ymthe.2017.04.022. Epub 2017 May 17.

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

Author information

1
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada. Electronic address: olagnier@biomed.au.dk.
2
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada; Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
3
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
4
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
5
Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
6
Pasteur Laboratory, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome 00161, Italy.
7
Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
8
NSU Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.
9
Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Pasteur Laboratory, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome 00161, Italy. Electronic address: john.hiscott@istitutopasteur.it.
11
Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada; Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: rongtuan.lin@mcgill.ca.

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.

KEYWORDS:

Nrf2; VSV; autophagy; cancer; innate antiviral response; interferon; oncolysis

PMID:
28527723
PMCID:
PMC5542709
DOI:
10.1016/j.ymthe.2017.04.022
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center