Nrf2: friend or foe for chemoprevention?

Abstract

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 ECH-associated 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.

Fig. 1.

General scheme for the induction of cytoprotective genes through the KEAP1–NRF2–ARE-signaling pathway. In the basal state (left panel), NRF2 exhibits low steady-state levels and rapid turnover due to ubiquitination and degradation by the proteasome. Chemopreventive inducers (right panel) such as phenolic antioxidants, oltipraz, sulforaphane and triterpenoids increase the nuclear translocation of NRF2 primarily through interactions with KEAP1 that impare ubiquitination of NRF2 and subsequent proteasomal degradation. Phosphorylation of NRF2 by a series of kinases also affects its fate and distribution. After translocation to the nucleus, NRF2 transactivates the AREs of cytoprotective genes affecting several protective systems, such as conjugating/detoxication enzymes, antioxidative enzymes, the proteasome, transporters, molecular chaperones and anti-inflammatory pathways. Detailed reviews of this pathway can be found in Kensler et al. (30), Dinkova-Kostova et al. (32), Tong et al. (33) and Hayes et al. (34).

Fig. 2.

Dose-response curves for the induction of NQO1, a prototypic NRF2-regulated gene, in murine Hepa1c1c7 cells by different classes of chemopreventive agents. Enzyme activity was assayed by the Prochaska assay (51). Values in parentheses indicated the concentrations required to double enzyme activity for each inducer (dashed line intercepts). SFN, sulforaphane.

Fig. 3.

(A) U-Shaped modulation of cancer risk through the KEAP1–NRF2 pathway. Optimal activation of the pathway lies in a pharmacological range between the biologically effective dose (BED) that minimally activates the pathway and a maximal-tolerated dose (MTD) that not only activates the pathway but also may produce dose-limiting ‘off target’ toxicities as well. Single-nucleotide polymorphisms (SNPs) in the Nrf2 promoter may diminish constitutive or inducible capacity of the pathway, whereas mutations or epigenetic silencing of Keap1 leads to sustained hyperactivation. (B) Comparison of the kinetics of induction of NRF2-regulated genes by pharmacological intervention versus genetic disruption of KEAP1 function. Chemopreventive agents that activate NRF2 signaling are typically administered (in both preclinical and clinical settings) on daily to weekly schedules, leading to pronounced but transient induction of downstream genes (dotted lines). In contrast, genetic disruption of the pathway, such as by conditional, tissue-specific targeted disruption of Keap1 (cKeap1) in the mouse or through somatic mutations acquired by cancer cells in KEAP1 or NRF2, leads to markedly elevated and sustained activation of the pathway (solid line). Chemopreventive agents cannot replicate the magnitude of response seen with genetic perturbation of the pathway (95).