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

被引：65

作者：

Olagnier, David ^{[1
,2
,10
]}

Lababidi, Rassin R. ^{[1
,2
,3
]}

Hadj, Samar Bel ^{[1
]}

Sze, Alexandre ^{[1
,2
]}

Liu, Yiliu ^{[1
,2
]}

Naidu, Sharadha Dayalan ^{[4
]}

Ferrari, Matteo ^{[9
]}

Jiang, Yuan ^{[1
,2
]}

Chiang, Cindy ^{[5
]}

Beljanski, Vladimir ^{[6
]}

Goulet, Marie-Line ^{[1
]}

Knatko, Elena V. ^{[4
]}

Dinkova-Kostova, Albena T. ^{[4
,7
,8
]}

Hiscott, John ^{[9
,11
]}

Lin, Rongtuan ^{[1
,2
,3
]}

机构：

[1] McGill Univ, Lady Davis Inst, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada

[2] McGill Univ, Div Expt Med, Montreal, PQ H4A 3J1, Canada

[3] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada

[4] Univ Dundee, Sch Med, Div Canc Res, Jacqui Wood Canc Ctr, Dundee DD1 9SY, Scotland

[5] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA

[6] Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA

[7] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[9] Ist Pasteur Fdn Cenci Bolognetti, Pasteur Lab, I-00161 Rome, Italy

[10] Aarhus Univ, Dept Biomed, Aarhus Res Ctr Innate Immunol, DK-8000 Aarhus C, Denmark

[11] Ist Pasteur Fdn Cenci Bolognetti, I-00161 Rome, Italy

来源：

MOLECULAR THERAPY | 2017年 / 25卷 / 08期

基金：

英国生物技术与生命科学研究理事会; 加拿大健康研究院;

关键词：

PROSTATE-CANCER CELLS; HEME OXYGENASE-1; CHEMOPREVENTIVE AGENTS; KAPPA-B; SULFORAPHANE; INHIBITION; INDUCTION; RESPONSES; BROCCOLI; ENZYMES;

D O I：

10.1016/j.ymthe.2017.04.022

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：1900 / 1916

页数：17

共 71 条

[1] Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production [J].

Alain, Tommy ;

Lun, XueQing ;

Martineau, Yvan ;

Sean, Polen ;

Pulendran, Bali ;

Petroulakis, Emmanuel ;

Zemp, Franz J. ;

Lemay, Chantal G. ;

Roy, Dominic ;

Bell, John C. ;

Thomas, George ;

Kozma, Sara C. ;

Forsyth, Peter A. ;

Costa-Mattioli, Mauro ;

Sonenberg, Nahum .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (04) :1576-1581

[2] ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS [J].

Alexander, Angela ;

Cai, Sheng-Li ;

Kim, Jinhee ;

Nanez, Adrian ;

Sahin, Mustafa ;

MacLean, Kirsteen H. ;

Inoki, Ken ;

Guan, Kun-Liang ;

Shen, Jianjun ;

Person, Maria D. ;

Kusewitt, Donna ;

Mills, Gordon B. ;

Kastan, Michael B. ;

Walker, Cheryl Lyn .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4153-4158

[3] Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo [J].

Altomonte, Jennifer ;

Wu, Lan ;

Chen, Li ;

Meseck, Marcia ;

Ebert, Oliver ;

Garcia-Sastre, Adolfo ;

Fallon, John ;

Woo, Savio L. C. .

MOLECULAR THERAPY, 2008, 16 (01) :146-153

[4] A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer [J].

Alumkal, Joshi J. ;

Slottke, Rachel ;

Schwartzman, Jacob ;

Cherala, Ganesh ;

Munar, Myrna ;

Graff, Julie N. ;

Beer, Tomasz M. ;

Ryan, Christopher W. ;

Koop, Dennis R. ;

Gibbs, Angela ;

Gao, Lina ;

Flamiatos, Jason F. ;

Tucker, Erin ;

Kleinschmidt, Richard ;

Mori, Motomi .

INVESTIGATIONAL NEW DRUGS, 2015, 33 (02) :480-489

[5] Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing [J].

Arulanandam, Rozanne ;

Batenchuk, Cory ;

Varette, Oliver ;

Zakaria, Chadi ;

Garcia, Vanessa ;

Forbes, Nicole E. ;

Davis, Colin ;

Krishnan, Ramya ;

Karmacharya, Raunak ;

Cox, Julie ;

Sinha, Anisha ;

Babawy, Andrew ;

Waite, Katherine ;

Weinstein, Erica ;

Falls, Theresa ;

Chen, Andrew ;

Hamill, Jeff ;

De Silva, Naomi ;

Conrad, David P. ;

Atkins, Harold ;

Garson, Kenneth ;

Ilkow, Carolina ;

Kaern, Mads ;

Vanderhyden, Barbara ;

Sonenberg, Nahum ;

Alain, Tommy ;

Le Boeuf, Fabrice ;

Bell, John C. ;

Diallo, Jean-Simon .

NATURE COMMUNICATIONS, 2015, 6

[6] Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex [J].

Baird, Liam ;

Lleres, David ;

Swift, Sam ;

Dinkova-Kostova, Albena T. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (38) :15259-15264

[7] Linear Ubiquitination of NEMO Negatively Regulates the Interferon Antiviral Response through Disruption of the MAVS-TRAF3 Complex [J].

Belgnaoui, S. Mehdi ;

Paz, Suzanne ;

Samuel, Sara ;

Goulet, Marie-Line ;

Sun, Qiang ;

Kikkert, Marjolein ;

Iwai, Kazuhiro ;

Dikic, Ivan ;

Hiscott, John ;

Lin, Rongtuan .

CELL HOST & MICROBE, 2012, 12 (02) :211-222

[8] Triptolide-Mediated Inhibition of Interferon Signaling Enhances Vesicular Stomatitis Virus-Based Oncolysis [J].

Ben Yebdri, Fethia ;

Van Grevenynghe, Julien ;

Tang, Vera A. ;

Goulet, Marie-Line ;

Wu, Jian Hui ;

Stojdl, David F. ;

Hiscott, John ;

Lin, Rongtuan .

MOLECULAR THERAPY, 2013, 21 (11) :2043-2053

[9] Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses [J].

Biswas, Chhanda ;

Shah, Nidhi ;

Muthu, Manasa ;

La, Ping ;

Fernando, Amal P. ;

Sengupta, Shaon ;

Yang, Guang ;

Dennery, Phyllis A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (39) :26882-26894

[10] Oncolytic Viruses: Therapeutics With an Identity Crisis [J].

Breitbach, Caroline J. ;

Lichty, Brian D. ;

Bell, John C. .

EBIOMEDICINE, 2016, 9 :31-36

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