Journal Article

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

Frese, Kristopher, Mangal, Dipti, Iacobuzio-Donahue, Christine, Wei, Cong, Hruban, Ralph H., Humpton, Timothy J., Yu, Kenneth H., Karreth, Florian A., Kern, Scott E., DeNicola, Gina M., Tuveson, David A., Yeo, Charles J., Scrimieri, Francesca, Gopinathan, Aarthi, Calhoun, Eric S., Winter, Jordan M., Blair, Ian A.

2011

Overview

Radical role reversal Reactive oxygen species (ROS), such as free radicals, are mutagenic and might therefore be expected to promote tumorigenesis. However, this work shows that expression of the oncogenes Kras , Braf and Myc at endogenous levels in mouse cells in fact reduces ROS levels. Some oncogenes are also shown to induce the transcription factor Nrf2, which acts to detoxify ROS. In line with this finding, deletion of Nrf2 impairs K-Ras-induced pancreatic tumour formation. Modulation of the redox state in cells thus seems to be an important factor in determining tumorigenic potential, and may be a possible target for therapy. Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer 1 . 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 6 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/319 / 631/67/395 / 692/420/755 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Alleles / Animal tissues / Animals / Antioxidants / Antioxidants - metabolism / Biological and medical sciences / Cancer / Carcinogenesis, carcinogens and anticarcinogens / Cell Line, Tumor / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cell Transformation, Neoplastic - pathology / Cells, Cultured / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Detoxification / Evacuations & rescues / Extracellular Signal-Regulated MAP Kinases - metabolism / Fibroblasts - metabolism / Gene expression / General aspects / Genes, myc - genetics / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / JNK Mitogen-Activated Protein Kinases - metabolism / Kelch-Like ECH-Associated Protein 1 / letter / MAP Kinase Signaling System / Mass spectrometry / Medical sciences / Mice / Mitogen-Activated Protein Kinase Kinases - metabolism / multidisciplinary / NF-E2-Related Factor 2 - deficiency / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / NIH 3T3 Cells / Oncogenes / Oncogenes - genetics / Oxidation-Reduction / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Physiological aspects / Polymerase chain reaction / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Proto-Oncogene Proteins p21(ras) - genetics / Proto-Oncogene Proteins p21(ras) - metabolism / Reactive oxygen species / Reactive Oxygen Species - metabolism / Rodents / Science / Science (multidisciplinary) / Studies / Tumors