Abstract
Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer1. 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-tumorigenic6. 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-RasG12D, B-RafV619E and MycERT2 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-RasG12D and B-RafV619E, and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-RasG12D-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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Acknowledgements
We thank J. Johnson for providing the Nrf2−/− mice; G. Evan, O. Sansom, C. Murtaugh, J.-J. Ventura and E. Wagner for MEFs; E. Schmidt for Nrf2 antiserum; E. Jaffee, A. Maitra and A. Horii for human PDA cell lines; B. Haynes, S. Davies and N. Cook for human PDA tissue samples; C. Ross-Innes, K. Holmes and J. Carroll for advice with the ChIP assay; and the ENCODE Consortium for ChIP-seq studies. We thank F. Connor, C. Martins and other members of the Tuveson lab for assistance and advice, and the animal care staff and histology core at CRI. This research was supported by the University of Cambridge and Cancer Research UK, The Li Ka Shing Foundation and Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Centre, and the NIH (grants CA101973, CA111294, CA084291 and CA105490 to D.A.T.; CA62924 and CA128920 to S.E.K. and C.I.-D.; and CA106610 to C.I.-D.). Additional support was obtained from the Abramson Cancer Center of the University of Pennsylvania Pilot Grant IRG 78-002-26 (D.A.T.), Emerald Foundation (E.S.C.), the Marjorie Kovler Fund (S.E.K.) and the Ruth L. Kirschstein National Research Service Award F32CA123887-01 (K.F.). We regret that many primary references have been omitted due to space limitations.
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G.M.D., F.A.K., T.J.H., A.G. and K.F. performed cell culture and mouse experiments. C.W., D.M., K.H.Y. and I.A.B. performed 8-oxo-dGuo and glutathione assays. C.J.Y., E.S.C., F.S., J.M.W., R.H.H., C.I.-D. and S.E.K. performed Nrf2 and Keap1 sequencing. G.M.D. and D.A.T. designed the study and wrote the manuscript, and all authors commented on it.
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DeNicola, G., Karreth, F., Humpton, T. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). https://doi.org/10.1038/nature10189
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DOI: https://doi.org/10.1038/nature10189