The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
Abstract
:1. Introduction
2. The Transcription Factor NRF2
2.1. NRF Family Members
2.2. Domains and Interactions
2.3. Mechanisms of NRF2 Activation and Inhibition
- (1)
- KEAP1 is the main repressor of NRF2 activation and is rich in redox-sensitive cysteine residues. Notably, Cys151, Cys273, and Cys288 in the KEAP1 protein are involved in the interaction with NRF2 [67]. During oxidative stress, these cysteine residues, functioning as ROS sensors, become oxidized, causing a structural alteration in KEAP1. In the canonical pathway, this oxidative change disrupts the hinge-and-latch complex and severs the connection with the NRF2 DLG pattern. Consequently, the NRF2–KEAP1 complex undergoes a conformational shift that prevents NRF2 ubiquitination [47,55].
- (2)
- Other proteins such as p21 or p62 can compete with KEAP1 for binding to the NRF2 DLG motif through the non-canonical pathway. This competitive binding results in a conformational change that hinders NRF2 degradation [68].
- (3)
- Different phosphorylation events involving NRF2 can lead to its dissociation from KEAP1. For instance, protein kinase C (PKC) induces phosphorylation of the Ser40 residue [69], which is situated in the Neh2 domain that interacts with KEAP1 [56]. This phosphorylation hinders the binding of NRF2 to KEAP1, preventing its sequestration by KEAP1.
- (4)
- The antioxidant iASPP competes with NRF2 for KEAP1 binding via a DLT motif and induces NRF2 activation [70].
- (5)
- NRF2 can undergo glycation, rendering it unstable and impairing its binding to small MAF proteins and transcriptional activation. Fructosamine-3-kinase (FN3K) can promote deglycation of the NRF2 protein [71].
- (6)
- NRF2 glutarylation, regulated by the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), enhances protein stability and transcriptional activity [72].
2.4. Genes Regulated by NRF2
- (1)
- Antioxidant proteins: NRF2 finely regulates redox homeostasis by controlling the expression of antioxidant enzymes and facilitating the production of glutathione (GSH). Some of these antioxidant proteins include biliverdin reductase B, ferritin, glutamate-cysteine ligase (GCL), superoxide dismutases (SODs), glutathione peroxidases (GPXs), peroxiredoxins (PRXs), and glutathione reductase (GR). Notably, GCL is a critical enzyme involved in the synthesis of the potent antioxidant GSH.
- (2)
- NADPH-regenerating enzymes: NRF2 plays a crucial role in governing metabolic reprogramming and the generation of NADPH, which is pivotal in cellular antioxidant systems. Key enzymes in this category include glucose-6-phosphate dehydrogenase (G6PD), malic enzyme 1 (ME1), and 6-phosphogluconate dehydrogenase (6PGD).
- (3)
- Cytoprotective proteins: NRF2 regulates important proteins like HO-1 and metallothioneins. HO-1 catalyzes the breakdown of heme, resulting in the production of various compounds, including biliverdin, carbon monoxide, and iron. The cytoprotective effect of HO-1 is mediated indirectly through the generation of biliverdin and the potent antioxidant bilirubin. Notably, HO-1 expression has been observed to be higher in NRF2 knockout K-rasG12V 293T cells compared to wild-type NRF2 cells, suggesting that these enzymes can also be regulated by other transcription factors and signaling pathways [80].
- (4)
- Phase 1 enzymes: Phase I metabolism involves the reduction, oxidation, or hydrolysis of molecules such as drugs or toxic compounds. NRF2 regulates a range of enzymes in this category, including alcohol dehydrogenases (ADHs), aldehyde dehydrogenases (ALDHs), cytochromes P450 (CYPs), NQO1, and carboxyl esterase (CES).
- (5)
- Phase 2 enzymes: NRF2-dependent conjugation reactions are crucial for the detoxification of various xenobiotics. These reactions are carried out by glutathione S-transferases (GSTs), sulfotransferases (SULTs), and UDP-glucuronosyl transferases (UGTs).
- (6)
- Transport proteins: NRF2 also regulates transport proteins such as multi-drug resistance-associated proteins (MRPs) and neutral amino acid transporters through ARE sequences in their promoters. MRPs play a role in drug resistance.
- (7)
- Chaperone proteins: Chaperone proteins are responsible for ensuring the proper three-dimensional folding of other proteins, thus facilitating their maturation. NRF2 regulates various chaperone proteins, including heat-shock proteins (HSPs).
- (8)
- Transcription factors: NRF2 regulates the expression of MAF proteins, as well as BACH1 and NRF2 itself, through the ARE sequences in their promoters.
2.5. NRF2: A Double-Edged Sword
2.5.1. NRF2: The Bright Side
2.5.2. NRF2: The Dark Side
3. NRF2 in the Context of Cancer Promotion
3.1. Pro-Oncogenic Functions of the KEAP1–NRF2 Pathway
3.2. Role of NRF2 in the Dysregulation of Cell Proliferation
3.3. Role of NRF2 in Tumor Metabolism
3.4. Role of NRF2 in Cell Death
4. Role of NRF2 and ROS on Some Critical Cellular Processes
4.1. NRF2 and ROS in Tumor Immunology
4.2. Interplays between NRF2, ROS and LncRNAs in Cancer
4.3. Crosstalk between NRF2 Activation and Phase Separation
4.4. Role of NRF2 and BACH1 in Cancer Stem Cells and Metastasis
5. NRF2 in Cancer Prevention and Its Therapeutic Implications
5.1. NRF2 Activators
5.2. NRF2 Inhibitors
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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NRF2 Activators | Modes of Action | References |
---|---|---|
Sulforaphane | Covalent binding to KEAP1 cysteine residues | [196,197] |
Triterpenoids (CDDO) | Target KEAP1 and activation of NRF2 response | [198,199] |
RA839 | Selective inhibitor of the KEAP1/NRF2 interaction | [200] |
MMF/DMF | Activation of NRF2 and upregulation of its target genes | [201,202,203] |
NRF2 Inhibitors | Modes of Action | References |
Bexarotene | Interaction with the Neh7 domain of NRF2 | [204,205,206] |
Brusatol | Global protein synthesis inhibitor | [207,208] |
Flavonoids | Increase in NRF2 instability | [209,210] |
Ochratoxin A | Interference with NRF2 translocation and its DNA binding | [211] |
Trigonelline | Reduced nuclear accumulation of the NRF2 protein | [212,213] |
Malabaricon-A | Inhibition of NRF2 transcriptional activity | [214] |
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Glorieux, C.; Enríquez, C.; González, C.; Aguirre-Martínez, G.; Buc Calderon, P. The Multifaceted Roles of NRF2 in Cancer: Friend or Foe? Antioxidants 2024, 13, 70. https://doi.org/10.3390/antiox13010070
Glorieux C, Enríquez C, González C, Aguirre-Martínez G, Buc Calderon P. The Multifaceted Roles of NRF2 in Cancer: Friend or Foe? Antioxidants. 2024; 13(1):70. https://doi.org/10.3390/antiox13010070
Chicago/Turabian StyleGlorieux, Christophe, Cinthya Enríquez, Constanza González, Gabriela Aguirre-Martínez, and Pedro Buc Calderon. 2024. "The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?" Antioxidants 13, no. 1: 70. https://doi.org/10.3390/antiox13010070