Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

By G. DeNicola, F. Karreth, Timothy J. Humpton, A. Gopinathan, Cong Wei, K. Frese, Dipti Mangal, Kenneth H. Yu, C. Yeo, Eric S. Calhoun and 7 more. Nature, 2011

2,178 citations recorded by the source corpus.

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-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.

Subfields: Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/f38b28c59cdc225a82c8cdb425c2616bdbb5d3af

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Citations in the corpus

Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells (2015, background): “For example, NRF2 prevents the initiation but accelerates the progression of chemical carcinogen-mediated or oncogene-mediated carcinogenesis.(9,10) NRF2 overexpression inhibits apoptosis and contributes to chemoresistance in several cancers.”
Autophagy: Renovation of Cells and Tissues (2011, background): “, 2009) and persistent activation of Nrf2 (DeNicola et al., 2011).”
KRAS: feeding pancreatic cancer proliferation (2014, neutral): “KRas(G12D) expression was shown to increase the transcription of NRF2, which through stable elevation of the basal Nrf2 antioxidant program, activates a ROS-detoxification program to confer a more reduced intracellular environment [50].”
Reactive Oxygen Species in Health and Disease (2012, background): “More recently, DeNicola and colleagues have demonstrated that in mice several endogenous oncogenes such as Kras, Braf, and Myc actively induce Nrf2 expression, promoting an ROS detoxification program and hence creating a more “reduced” intracellular environment, a program that the authors suggest to”
ROS Function in Redox Signaling and Oxidative Stress (2014, background): “The loss of NRF2 in cancer cells increases oxidative stress, resulting in diminished tumorigenesis [50].”
Oxidative Stress in Cancer (2020, background): “For example, the incidence of pancreatic cancer was markedly reduced in Nrf2-null mice relative to wild-type mice in a K-RasG12D-driven cancer model (DeNicola et al., 2011), and the incidence of lung tumors in Nrf2-null mice was also modestly reduced relative to wild-type mice in urethane-initiated ”
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