Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
Open accessAbstract
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.
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Established oncogenes K-RAS and c-MYC induce intracellular ROS and have been shown to stabilize Nrf2.
“Moreover, established oncogenes such as K-RAS and c-MYC, which had been previously demonstrated to induce intracellular ROS56,57, have been recently shown to stabilize Nrf258.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [58]
The citation to this paper attaches to the claim that K-RAS and c-MYC stabilize Nrf2, not to the earlier ROS claim. Our copy says these oncogenes increase Nrf2 transcription; it distinguishes that mechanism from increased Nrf2 stability caused by Nrf2 or Keap1 mutations (passages 2 and 8, section labeled Abstract). (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredNrf2 mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation.
“For example, the transcription factor Nrf2, which mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation (Chio et al., 2016; DeNicola et al., 2011).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as DeNicola et al., 2011
Oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression and constitutively activating NRF2-controlled genes to maintain redox balance and promote tumorigenesis.
“In addition to activating the GOT2/GOT1/Malic Enzyme 1 (ME1) pathway, oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression59,60 and by constitutively activating the battery of genes controlled by NRF2 to maintain the redox balance and promote tumorigenesis61.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [59]
BRAF mutants can activate NRF2 to promote ROS detoxification.
“The activation of NRF2 causes glutamine dependence in KRAS mutant lung and pancreatic cancers cells and preclinical mouse models60,62,63, and BRAF mutants can similarly activate NRF2 to promote reactive oxygen species (ROS) detoxification59.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [59]
Ectopic overexpression of oncogenic RAS mutants increased basal ROS levels in fibroblasts through a RAF-MEK-MAPK-NOX pathway.
“ectopic overexpression of oncogenic RAS mutants increased basal ROS levels in fibroblasts, through a RAF-MEK-MAPK-NOX pathway”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [73]
Mutations in endogenous RAS alleles without overexpression upregulated NRF2, which induces antioxidant genes and enhances ROS-detoxifying capacity.
“mutations in the endogenous RAS alleles (without overexpression) upregulated NRF2, a transcription factor that induces expression of antioxidant genes, enhancing the ROS-detoxifying capacity of the cells [73].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [73]
KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine-glycine biosynthetic pathways with enhanced dependence on glutaminolysis for TCA cycle anaplerosis, a dependence further enhanced by co-occurring LKB1 alterations.
“At the cellular level KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine–glycine biosynthetic pathways93–95 with enhanced dependence on glutaminolysis for tricarboxylic acid (TCA) cycle anaplerosis92, a dependence that is further enhanced by co-occurring LKB1”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [95]
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- Authors
- DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., Scrimieri, F., Winter, J. M., Hruban, R. H., Iacobuzio-Donahue, C., Kern, S. E., Blair, I. A., & Tuveson, D. A.
- Affiliations
- Cancer Research UK (GB)
- University of Vienna (AT)
- University of Pennsylvania (US)
- Alma College (US)
- Johns Hopkins University (US)
- Corresponding author
- Tuveson, David A.
- ORCID
- Venue
- Nature
- Published
- 2011-07
- Volume
- 475
- Issue
- 7354
- Pages
- 106-109
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3404470
- OpenAlex
- W1992724001
- Cited by
- 2,277
- References
- 30
- Citations by year
- 2026: 117 · 2025: 117 · 2024: 162 · 2023: 185 · 2022: 198 · 2021: 192 · 2020: 187 · 2019: 186 · 2018: 152 · 2017: 136 · 2016: 141 · 2015: 131 · 2014: 130 · 2013: 114 · 2012: 106
- FWCI
- 47.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- ResearchOnline (Glasgow Caledonian University) (acceptedVersion)
- The Medicine Forum (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research UK
- National Cancer Institute (CA101973, CA105490, K08CA106610, CA111294, U01CA084291, U01CA105490, F32CA123887, CA106610, R01CA101973, CA084291, U01CA111294, R01CA128920, P50CA062924, CA128920, CA 62924)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- Nrf2, reactive oxygen species, oncogenes, KRAS, BRAF, c-Myc, reactive oxygen species scavenging, antioxidant response, carcinogenesis, pancreatic cancer, KRAS G12D, redox state, oxidative stress
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Alleles, Animals, Antioxidants, Cell Transformation, Neoplastic, Cells, Cultured, Cytoskeletal Proteins, Fibroblasts, Humans, Oncogenes, Oxidation-Reduction, Pancreatic Neoplasms, Genes, myc, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, NIH 3T3 Cells, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, Cell Proliferation, NF-E2-Related Factor 2, Mice
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