NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

被引：301

作者：

Chio, Iok In Christine ^{[1
,2
]}

Jafarnejad, Seyed Mehdi ^{[3
,4
]}

Ponz-Sarvise, Mariano ^{[1
,2
,12
]}

Park, Youngkyu ^{[1
,2
]}

Rivera, Keith ^{[1
]}

Palm, Wilhelm ^{[5
]}

Wilson, John ^{[1
]}

Sangar, Vineet ^{[6
]}

Hao, Yuan ^{[1
]}

Oehlund, Daniel ^{[1
,2
]}

Wright, Kevin ^{[1
,2
]}

Filippini, Dea ^{[1
,2
]}

Lee, Eun Jung ^{[1
,2
]}

Da Silva, Brandon ^{[1
,2
]}

Schoepfer, Christina ^{[1
,2
]}

Wilkinson, John Erby ^{[7
,8
]}

Buscaglia, Jonathan M. ^{[9
]}

DeNicola, Gina M. ^{[10
]}

Tiriac, Herve ^{[1
,2
]}

Hammell, Molly ^{[1
]}

Crawford, Howard C. ^{[7
,8
]}

Schmidt, Edward E. ^{[11
]}

Thompson, Craig B. ^{[5
]}

Pappin, Darryl J. ^{[1
]}

Sonenberg, Nahum ^{[3
,4
]}

Tuveson, David A. ^{[1
,2
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] Lustgarten Fdn Pancreat Canc Res Lab, Cold Spring Harbor, NY 11724 USA

[3] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada

[4] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[5] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[6] Inst Syst Biol, 401 Terry Ave N, Seattle, WA 98109 USA

[7] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[9] SUNY Stony Brook, Sch Med, Dept Med, Div Gastroenterol, Stony Brook, NY 11794 USA

[10] Weill Cornell Med Coll, Meyer Canc Ctr, New York, NY 10021 USA

[11] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59718 USA

[12] Univ Navarra Clin, CIMA, IDISNA, Dept Oncol, Pamplona 31008, Spain

来源：

CELL | 2016年 / 166卷 / 04期

基金：

瑞典研究理事会;

关键词：

SIGNALING PATHWAYS; DUCTAL ADENOCARCINOMA; OXIDATIVE STRESS; REDOX PROTEOMICS; INITIATION; KRAS; RAS; COMPLEX; KINASE; AKT;

D O I：

10.1016/j.cell.2016.06.056

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

引用

页码：963 / 976

页数：14

共 55 条

[1] Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses [J].

Anastasiou, Dimitrios ;

Poulogiannis, George ;

Asara, John M. ;

Boxer, Matthew B. ;

Jiang, Jian-kang ;

Shen, Min ;

Bellinger, Gary ;

Sasaki, Atsuo T. ;

Locasale, Jason W. ;

Auld, Douglas S. ;

Thomas, Craig J. ;

Vander Heiden, Matthew G. ;

Cantley, Lewis C. .

SCIENCE, 2011, 334 (6060) :1278-1283

[2] EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis [J].

Ardito, Christine M. ;

Gruener, Barbara M. ;

Takeuchi, Kenneth K. ;

Lubeseder-Martellato, Clara ;

Teichmann, Nicole ;

Mazur, Pawel K. ;

DelGiorno, Kathleen E. ;

Carpenter, Eileen S. ;

Halbrook, Christopher J. ;

Hall, Jason C. ;

Pal, Debjani ;

Briel, Thomas ;

Herner, Alexander ;

Trajkovic-Arsic, Marija ;

Sipos, Bence ;

Liou, Geou-Yarh ;

Storz, Peter ;

Murray, Nicole R. ;

Threadgill, David W. ;

Sibilia, Maria ;

Washington, M. Kay ;

Wilson, Carole L. ;

Schmid, Roland M. ;

Raines, Elaine W. ;

Crawford, Howard C. ;

Siveke, Jens T. .

CANCER CELL, 2012, 22 (03) :304-317

[3] The role of cysteine residues as redox-sensitive regulatory switches [J].

Barford, D .

CURRENT OPINION IN STRUCTURAL BIOLOGY, 2004, 14 (06) :679-686

[4] INDUCTION OF MEMBRANE RUFFLING AND FLUID-PHASE PINOCYTOSIS IN QUIESCENT FIBROBLASTS BY RAS PROTEINS [J].

BARSAGI, D ;

FERAMISCO, JR .

SCIENCE, 1986, 233 (4768) :1061-1068

[5]

Belalcazar Andrea D, 2014, ISRN Biochem, V2013, P637897

[6] Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies [J].

Bilanges, B. ;

Stokoe, D. .

ONCOGENE, 2007, 26 (41) :5973-5990

[7] Organoid Models of Human and Mouse Ductal Pancreatic Cancer [J].

Boj, Sylvia F. ;

Hwang, Chang-Il ;

Baker, Lindsey A. ;

Chio, Iok In Christine ;

Engle, Dannielle D. ;

Corbo, Vincenzo ;

Jager, Myrthe ;

Ponz-Sarvise, Mariano ;

Tiriac, Herve ;

Spector, Mona S. ;

Gracanin, Ana ;

Oni, Tobiloba ;

Yu, Kenneth H. ;

van Boxtel, Ruben ;

Huch, Meritxell ;

Rivera, Keith D. ;

Wilson, John P. ;

Feigin, Michael E. ;

Oehlund, Daniel ;

Handly-Santana, Abram ;

Ardito-Abraham, Christine M. ;

Ludwig, Michael ;

Elyada, Ela ;

Alagesan, Brinda ;

Biffi, Giulia ;

Yordanov, Georgi N. ;

Delcuze, Bethany ;

Creighton, Brianna ;

Wright, Kevin ;

Park, Youngkyu ;

Morsink, Folkert H. M. ;

Molenaar, I. Quintus ;

Rinkes, Inne H. Borel ;

Cuppen, Edwin ;

Hao, Yuan ;

Jin, Ying ;

Nijman, Isaac J. ;

Iacobuzio-Donahue, Christine ;

Leach, Steven D. ;

Pappin, Darryl J. ;

Hammell, Molly ;

Klimstra, David S. ;

Basturk, Olca ;

Hruban, Ralph H. ;

Offerhaus, George Johan ;

Vries, Robert G. J. ;

Clevers, Hans ;

Tuveson, David A. .

CELL, 2015, 160 (1-2) :324-338

[8] Using Quantitative Redox Proteomics to Dissect the Yeast Redoxome [J].

Brandes, Nicolas ;

Reichmann, Dana ;

Tienson, Heather ;

Leichert, Lars I. ;

Jakob, Ursula .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (48) :41893-41903

[9] Not all substrates are treated equally Implications for mTOR, rapamycin-resistance and cancer therapy [J].

Choo, Andrew Y. ;

Blenis, John .

CELL CYCLE, 2009, 8 (04) :567-572

[10] AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases:: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models [J].

Davies, Barry R. ;

Logie, Armelle ;

McKay, Jennifer S. ;

Martin, Paul ;

Steele, Samantha ;

Jenkins, Richard ;

Cockerill, Mark ;

Cartlidge, Sue ;

Smith, Paul D. .

MOLECULAR CANCER THERAPEUTICS, 2007, 6 (08) :2209-2219

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