Journal
MOLECULAR THERAPY
Volume 25, Issue 8, Pages 1900-1916Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.04.022
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Funding
- Canadian Institutes of Health Research grant [MOP130401]
- Prostate Cancer Research Foundation of Canada grant [D2013-23]
- Fondazione Cenci Bolognetti
- NIH [1R21CA192185- 01]
- Italian Association for Cancer Research [AIRC-AG16901]
- Cancer Research UK [C20953/A18644]
- BBSRC [BB/L01923X/1]
- Peter Quinlan McGill Postdoctoral Fellowship
- Canadian Cancer Society Travel Award grant
- Fond de la Recherche Sante Quebec (FRSQ) Fellowship award
- Biotechnology and Biological Sciences Research Council [BB/L01923X/1] Funding Source: researchfish
- Cancer Research UK [18644] Funding Source: researchfish
- BBSRC [BB/L01923X/1] Funding Source: UKRI
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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 Delta 51 (VSV Delta 51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSV Delta 51 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 VSV Delta 51 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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