NRF2 Promotes Tumor Maintenance by Modulating MRNA Translation in Pancreatic Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Aug 2

PMID 27477511

Citations 214

Authors

Iok In Christine Chio

Seyed Mehdi Jafarnejad

Mariano Ponz-Sarvise

Youngkyu Park

Keith Rivera

Wilhelm Palm

John Wilson

Vineet Sangar

Yuan Hao

Daniel Ohlund

Kevin Wright

Dea Filippini

Eun Jung Lee

Brandon Da Silva

Christina Schoepfer

John Erby Wilkinson

Jonathan M Buscaglia

Gina M DeNicola

Herve Tiriac

Molly Hammell

Howard C Crawford

Edward E Schmidt

Craig B Thompson

Darryl J Pappin

Nahum Sonenberg

David A Tuveson

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Thirty years of NRF2: advances and therapeutic challenges.

Zhang D Nat Rev Drug Discov. 2025; .

PMID: 40038406 DOI: 10.1038/s41573-025-01145-0.

Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin.

Yang Z, Han T, Yang R, Zhang Y, Qin Y, Hou J Front Immunol. 2025; 16:1531874.

PMID: 40007539 PMC: 11852437. DOI: 10.3389/fimmu.2025.1531874.

OASL promotes immune evasion in pancreatic ductal adenocarcinoma by enhancing autolysosome-mediated degradation of MHC-I.

Xing X, Li X, Yin S, Ma H, Xiao S, Tulamaiti A Theranostics. 2025; 15(6):2104-2120.

PMID: 39990208 PMC: 11840728. DOI: 10.7150/thno.103494.

Yang Y, Yu S, Liu W, Zhuo Y, Qu C, Zeng Y Cancer Drug Resist. 2025; 8:1.

PMID: 39935430 PMC: 11813627. DOI: 10.20517/cdr.2024.151.

Spatially defined microenvironment for engineering organoids.

Zhang Y, Qi F, Chen P, Liu B, Li Y Biophys Rev (Melville). 2024; 5(4):041302.

PMID: 39679203 PMC: 11646138. DOI: 10.1063/5.0198848.

References

Permyakov S, Zernii E, Knyazeva E, Denesyuk A, Nazipova A, Kolpakova T . Oxidation mimicking substitution of conservative cysteine in recoverin suppresses its membrane association. Amino Acids. 2011; 42(4):1435-42. DOI: 10.1007/s00726-011-0843-0. View

Ruggero D, Sonenberg N . The Akt of translational control. Oncogene. 2005; 24(50):7426-34. DOI: 10.1038/sj.onc.1209098. View

Davies B, Logie A, McKay J, Martin P, Steele S, Jenkins R . 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.... Mol Cancer Ther. 2007; 6(8):2209-19. DOI: 10.1158/1535-7163.MCT-07-0231. View

Palm W, Park Y, Wright K, Pavlova N, Tuveson D, Thompson C . The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1. Cell. 2015; 162(2):259-270. PMC: 4506698. DOI: 10.1016/j.cell.2015.06.017. View

Ke B, Shen X, Zhang Y, Ji H, Gao F, Yue S . KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J Hepatol. 2013; 59(6):1200-7. PMC: 4524560. DOI: 10.1016/j.jhep.2013.07.016. View

Otto G, Puglisi J . The pathway of HCV IRES-mediated translation initiation. Cell. 2004; 119(3):369-80. DOI: 10.1016/j.cell.2004.09.038. View

Sayin V, Ibrahim M, Larsson E, Nilsson J, Lindahl P, Bergo M . Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014; 6(221):221ra15. DOI: 10.1126/scitranslmed.3007653. View

Raught B, Gingras A, Gygi S, Imataka H, Morino S, Gradi A . Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J. 2000; 19(3):434-44. PMC: 305580. DOI: 10.1093/emboj/19.3.434. View

Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R . Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol Cell Biol. 2004; 24(15):6539-49. PMC: 444855. DOI: 10.1128/MCB.24.15.6539-6549.2004. View

10.

Moore P, Sipos B, Orlandini S, Sorio C, Real F, Lemoine N . Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch. 2002; 439(6):798-802. DOI: 10.1007/s004280100474. View

11.

Talalay P, Fahey J, Healy Z, Wehage S, Benedict A, Min C . Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci U S A. 2007; 104(44):17500-5. PMC: 2077285. DOI: 10.1073/pnas.0708710104. View

12.

Malec V, Gottschald O, Li S, Rose F, Seeger W, Hanze J . HIF-1 alpha signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells. Free Radic Biol Med. 2010; 48(12):1626-35. DOI: 10.1016/j.freeradbiomed.2010.03.008. View

13.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M . Cancer statistics, 2009. CA Cancer J Clin. 2009; 59(4):225-49. DOI: 10.3322/caac.20006. View

14.

Johnson L, G Williams J, Abelson H, Green H, Penman S . Changes in RNA in relation to growth of the fibroblast. III. Posttranscriptional regulation of mRNA formation in resting and growing cells. Cell. 1975; 4(1):69-75. DOI: 10.1016/0092-8674(75)90135-x. View

15.

Wilson J, Powell M, Hoover S, Sarnow P . Naturally occurring dicistronic cricket paralysis virus RNA is regulated by two internal ribosome entry sites. Mol Cell Biol. 2000; 20(14):4990-9. PMC: 85949. DOI: 10.1128/MCB.20.14.4990-4999.2000. View

16.

Brandes N, Reichmann D, Tienson H, Leichert L, Jakob U . Using quantitative redox proteomics to dissect the yeast redoxome. J Biol Chem. 2011; 286(48):41893-41903. PMC: 3308895. DOI: 10.1074/jbc.M111.296236. View

17.

Molife L, Yan L, Vitfell-Rasmussen J, Zernhelt A, Sullivan D, Cassier P . Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol. 2014; 7:1. PMC: 3884022. DOI: 10.1186/1756-8722-7-1. View

18.

Hayes J, Dinkova-Kostova A . The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014; 39(4):199-218. DOI: 10.1016/j.tibs.2014.02.002. View

19.

Mendoza M, Er E, Blenis J . The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011; 36(6):320-8. PMC: 3112285. DOI: 10.1016/j.tibs.2011.03.006. View

20.

Anastasiou D, Poulogiannis G, Asara J, Boxer M, Jiang J, Shen M . Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science. 2011; 334(6060):1278-83. PMC: 3471535. DOI: 10.1126/science.1211485. View