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Sci. Signal., 12 July 2011
Vol. 4, Issue 181, p. ec192
[DOI: 10.1126/scisignal.4181ec192]

EDITORS' CHOICE

Cancer Regulating ROS for Tumorigenicity

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Reactive oxygen species (ROS) can elicit DNA damage and activate inflammatory pathways, suggesting a role for them in promoting cancer and, conversely, a protective role for antioxidants. However, mutations that stabilize the transcription factor NRF2, thereby activating an antioxidant program that confers protection against oxidative stress, have been identified in certain cancers (see Perera and Bardeesy). DeNicola et al. found that, whereas ectopic overexpression of an oncogenic form of K-Ras in mouse fibroblasts led to increased ROS, cells engineered to express moderate amounts of oncogenic K-Ras ("endogenous oncogenic K-Ras") had decreased ROS abundance. ROS abundance was also decreased in cells expressing "endogenous" oncogenic Myc. The ability of endogenous oncogenic K-Ras to decrease ROS and to promote a more reduced cellular environment depended on Nrf2; moreover, endogenous oncogenic K-Ras or endogenous oncogenic Myc increased the abundance of Nrf2 mRNA and protein, and that of its target genes. Exploration of downstream components of Ras signaling revealed that endogenous oncogenic B-Raf increased Nrf2 mRNA and decreased ROS abundance, and that pharmacological inhibition of MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) decreased the induction of Nrf2 and its target genes and restored ROS abundance in cells with endogenous oncogenic K-Ras. K-Ras and B-Raf signaled through ERK (extracellular signal-regulated kinase), rather than p38, to activate Nrf2 transcription by means of Jun and Myc. Abundance of the Nrf2 target Nqo1 was increased in K-Ras mutant pre-invasive pancreatic intraepithelial neoplasia (PanIN), whereas abundance of both a DNA oxidation product and of a lipid peroxidation adduct were decreased (indicative of decreased ROS). PanIN from Nrf2–/– mice showed decreased proliferation compared with PanIN from Nrf2+/+ mice, and the PanIN from Nrf2–/– mice had more cells with a senescence-associated phenotype (β-galactosidase activity). Moreover, administration of the antioxidant N-acetyl cysteine rescued the PanIN proliferation defect in Nrf2–/– mice. Similarly, in a mouse model of K-Ras mutant-mediated lung tumorigenesis, Nrf2–/– mice showed decreased disease burden and proliferation compared with Nrf2+/+ mice, and increased survival. Thus, the authors conclude that oncogenes can activate a ROS-detoxification program that can promote tumorigenesis.

G. M. DeNicola, F. A. Karreth, T. J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K. H. Yu, C. J. Yeo, E. S. Calhoun, F. Scrimieri, J. M. Winter, R. H. Hruban, C. Iacobuzio-Donahue, S. E. Kern, I. A. Blair, D. A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). [PubMed]

R. M. Perera, N. Bardeesy, When antioxidants are bad. Nature 475, 43–44 (2011). [PubMed]

Citation: E. M. Adler, Regulating ROS for Tumorigenicity. Sci. Signal. 4, ec192 (2011).



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