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Review
. 2012 Jul 19;12(8):564-71.
doi: 10.1038/nrc3278.

NRF2 and cancer: the good, the bad and the importance of context

Michael B Sporn  1 , Karen T Liby
Affiliations
Review

NRF2 and cancer: the good, the bad and the importance of context

Michael B Sporn et al. Nat Rev Cancer. .

Abstract

Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.

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Figures

Figure 1
Figure 1. Suppression of NRF2 activity by KEAP1, and disruption by drugs or mutations
Regulation of ubiquitylation of NFE2-related factor 2 (NRF2) is a key process in the cellular response to drugs or oxidative and electrophilic stress. a | In a basal state, in the absence of drugs or oxidative or electrophilic stress, NRF2 is polyubiquitylated by the Kelch-like ECH-associated protein 1 (KEAP1)– cullin 3 (CUL3) complex. CUL3 is a ubiquitin ligase and KEAP1 is a substrate adaptor. This polyubiquitylation results in NRF2 being degraded by the proteasome. b | The ubiquitylation of NRF2 is blocked when KEAP1 is rendered non-functional by the conformational change resulting from the binding of a drug or another electrophile to one of the reactive cysteine residues of KEAP1, or by the mutation of KEAP1. Two mechanisms have been suggested for this inactivation, namely: a ‘hinge and latch’ process, which loosens the association of NRF2 with KEAP1; or dissociation of CUL3 from KEAP1. Note that ubiquitylation of NRF2 can also be blocked by mutations in NRF2 (not shown). If NRF2 is not degraded, it can then migrate to the nucleus, where it becomes transcriptionally active after binding with one of the MAF proteins. Recent studies also suggest that interactions between NRF2–KEAP1 and a drug may occur in the nucleus , and that KEAP1 may also be regulated by ubiquitylation (not shown). This figure is a greatly simplified representation of a complex process; molecular details are still being elucidated . ARE, antioxidant response element.
Figure 1
Figure 1. Suppression of NRF2 activity by KEAP1, and disruption by drugs or mutations
Regulation of ubiquitylation of NFE2-related factor 2 (NRF2) is a key process in the cellular response to drugs or oxidative and electrophilic stress. a | In a basal state, in the absence of drugs or oxidative or electrophilic stress, NRF2 is polyubiquitylated by the Kelch-like ECH-associated protein 1 (KEAP1)– cullin 3 (CUL3) complex. CUL3 is a ubiquitin ligase and KEAP1 is a substrate adaptor. This polyubiquitylation results in NRF2 being degraded by the proteasome. b | The ubiquitylation of NRF2 is blocked when KEAP1 is rendered non-functional by the conformational change resulting from the binding of a drug or another electrophile to one of the reactive cysteine residues of KEAP1, or by the mutation of KEAP1. Two mechanisms have been suggested for this inactivation, namely: a ‘hinge and latch’ process, which loosens the association of NRF2 with KEAP1; or dissociation of CUL3 from KEAP1. Note that ubiquitylation of NRF2 can also be blocked by mutations in NRF2 (not shown). If NRF2 is not degraded, it can then migrate to the nucleus, where it becomes transcriptionally active after binding with one of the MAF proteins. Recent studies also suggest that interactions between NRF2–KEAP1 and a drug may occur in the nucleus , and that KEAP1 may also be regulated by ubiquitylation (not shown). This figure is a greatly simplified representation of a complex process; molecular details are still being elucidated . ARE, antioxidant response element.
Figure 2
Figure 2. A model for the importance of the context of tumour stage for the biological consequences of NRF2 activation
Enhancing NFE2-related factor 2 (NRF2) activity is important for the prevention of cancer, especially if low doses of drugs are used during the earliest stages of carcinogenesis. However, in fully malignant cells, enhancement of NRF2 activity (caused by mutations) can protect tumours from the cytotoxic effects of reactive oxygen species (ROS) that are induced by chemotherapy or that may be produced endogenously by oncogenic signalling in advanced tumours. The effects of NRF2 inducers on cells at intermediate stages of tumorigenesis are still largely unknown and need further investigation. Carcinogenesis is a continuum, and there may be many different premalignant genotypes and phenotypes within a given susceptible organ in vivo.
Figure 3
Figure 3. Beneficial or carcinogenic effects of fumarate depend on its dose and the presence or absence of the enzyme fumarate hydratase
In normal tissue, the Krebs cycle enzyme fumarate hydratase catalyses the rapid attack of water on the double bond of fumarate, resulting in the formation of malate. Intracellular levels of fumarate are thus kept low in the energy-producing process of the Krebs cycle. However, when fumarate hydratase is mutated and therefore inactive, the concentration of fumarate increases, and it is then susceptible to non-enzymatic attack by cysteine (as the thiolate anion). Reactive cysteine residues (such as Cys151) on the Kelch-like ECH-associated protein 1 (KEAP1) molecule can thus form covalent succinate adducts. This results in a conformational change in KEAP1 and transcriptional activation of NFE2-related factor 2 (NRF2), as shown in FIG. 1. The classic-α,β-unsaturated ketone (eneone) structure of the fumarate molecule is paradigmatic for many other drugs that activate NRF2. Figure courtesy of G. Gribble, Dartmouth College, Hanover, New Hampshire, USA.
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