Carcinogenesis Advance Access published online on September 30, 2009
Carcinogenesis, doi:10.1093/carcin/bgp231
Nrf2: Friend or Foe for Chemoprevention?
1 Department of Environmental Health Sciences, Bloomberg School of Public Health
2 Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205
3 Current address: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260
* To whom correspondence should be addressed. Email: tkensler{at}jhsph.edu
Health reflects the ability of an organism to adapt to stress. Stresses – metabolic, proteotoxic, mitotic, oxidative and DNA-damage stresses – not only contribute to the etiology of cancer and other chronic degenerative diseases, but are also hallmarks of the cancer phenotype. Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses, and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whilst disruption of the pathway exacerbates these outcomes. This pathway can be induced by thiol-reactive small molecules that demonstrate protective efficacy in preclinical chemoprevention models and in clinical trials. However, mutations and epigenetic modifications affecting the regulation and fate of NRF2 can lead to constitutive dominant hyper-activation of signaling that preserves rather than attenuates cancer phenotypes by providing selective resistance to stresses. This review provides a synopsis of KEAP1-NRF2 signaling, compares the impact of genetic versus pharmacologic activation, and considers both the attributes and concerns of targeting the pathway in chemoprevention.
Key Words: Chemoprevention • Nrf2 • keap1 • adaptive response
Received September 2, 2009; revised September 16, 2009; accepted September 18, 2009.