title: NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Iok In Christine
authors.initials: IIC
authors.lastname: Chio
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Jafarnejad
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ponz-Sarvise
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Youngkyu
authors.initials: Y
authors.lastname: Park
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Rivera
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Palm
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Institute of Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Sangar
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Öhlund
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wright
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Dea
authors.initials: D
authors.lastname: Filippini
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Da Silva
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Schoepfer
authors.affiliation: Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Buscaglia
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: DeNicola
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Herve
authors.initials: H
authors.lastname: Tiriac
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Hammell
authors.affiliation: Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Pappin
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009940:Organoids / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D005978:Glutathione; D003545:Cysteine