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Cell. 2016 Aug 11;166(4):963-976. doi: 10.1016/j.cell.2016.06.056. Epub 2016 Jul 28.

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
4
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Institute of Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
6
Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
7
Division of Gastroenterology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
8
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
9
Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718, USA.
10
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu.

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.

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PMID:
27477511
PMCID:
PMC5234705
DOI:
10.1016/j.cell.2016.06.056
[Indexed for MEDLINE]
Free PMC Article

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