title: Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.
abstract: Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.
authors: Li Ka Shing Centre, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors: Gina M
authors: GM
authors: DeNicola
authors: Florian A
authors: FA
authors: Karreth
authors: Timothy J
authors: TJ
authors: Humpton
authors: Aarthi
authors: A
authors: Gopinathan
authors: Cong
authors: C
authors: Wei
authors: Kristopher
authors: K
authors: Frese
authors: Dipti
authors: D
authors: Mangal
authors: Kenneth H
authors: KH
authors: Yu
authors: Charles J
authors: CJ
authors: Yeo
authors: Eric S
authors: ES
authors: Calhoun
authors: Francesca
authors: F
authors: Scrimieri
authors: Jordan M
authors: JM
authors: Winter
authors: Ralph H
authors: RH
authors: Hruban
authors: Christine
authors: C
authors: Iacobuzio-Donahue
authors: Scott E
authors: SE
authors: Kern
authors: Ian A
authors: IA
authors: Blair
authors: David A
authors: DA
authors: Tuveson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009857:Oncogenes / Q000235:genetics*; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)