Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)106-110
Number of pages5
JournalNature
Volume475
Issue number7354
DOIs
StatePublished - Jul 7 2011

ASJC Scopus subject areas

  • General

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