TY - JOUR
T1 - Nrf2
T2 - Friend or foe for chemoprevention?
AU - Kensler, Thomas W.
AU - Wakabayashi, Nobunao
PY - 2009/9/30
Y1 - 2009/9/30
N2 - 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 Kelch-like ECHassociated protein 1 (KEAP1)-NF-E2-related factor 2 (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 hyperactivation 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.
AB - 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 Kelch-like ECHassociated protein 1 (KEAP1)-NF-E2-related factor 2 (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 hyperactivation 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.
UR - http://www.scopus.com/inward/record.url?scp=74049120454&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=74049120454&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgp231
DO - 10.1093/carcin/bgp231
M3 - Review article
C2 - 19793802
AN - SCOPUS:74049120454
SN - 0143-3334
VL - 31
SP - 90
EP - 99
JO - Carcinogenesis
JF - Carcinogenesis
IS - 1
M1 - bgp231
ER -