The KEAP1-NRF2 System in Cancer

Abstract

Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anticancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anticancer agents or even NRF2 inhibitors.

Keywords: KEAP1; NRF2; cancer; cancer therapy; metabolic reprogramming.

Figure 1

KEAP1 and NRF2. (A) Two KEAP1 molecules and one NRF2 form a trimer through the DC domain in KEAP1 and the DLG and ETGE motifs within the N-terminal Neh2 domain of NRF2. This two-site binding of NRF2 and KEAP1 has been shown to be the molecular basis of electrophile-induced NRF2 accumulation. (B) The ratio of KEAP1:NRF2 binding. KEAP1 is unable to bind a large amount of NRF2.

Figure 2

KEAP1–NRF2 system. KEAP1-CUL3 directly binds NRF2, which is then rapidly degraded by the 26S proteasome in the cytoplasm. NRF2 that escapes KEAP1 trapping is stabilized and accumulates in the nucleus. GSK3 phosphorylates the Neh6 domain of NRF2. Phosphorylated NRF2 binds β-TrCP-CUL1 and is then degraded by the 26S proteasome in the nucleus. NRF2 forms a heterodimer with sMAF and binds CNC-sMAF-binding elements (CsMBE), including the consensus ARE/EpRE sequence, TGACNNNGC. NRF2 upregulates cytoprotective genes encoding antioxidant enzymes and detoxifying enzymes.

Figure 3

Difference in NRF2 activation between normal cells and NRF2-addicted cancer cells. (A) Unstressed condition. The intracellular NRF2 level is very low in normal cells. In contrast, constitutive NRF2 activation in cancer cells accelerates proliferation and metabolism. (B) Oxidative stress-exposed condition. In normal cells, the cellular NRF2 level is temporarily increased upon exposure to toxic (often electrophilic) chemicals and ROS. In contrast, constitutive NRF2 activation confers resistance on cancer cells to anticancer drugs and radiation.

Figure 4

Distribution of somatic mutations in the NRF2 gene in cancers. (A) NRF2 mutations in the exDLG and ETGE motifs. Red lines indicate the DLG motif and the ETGE motif. Please see Ref. (10). (B) The domain structure of the NRF2 protein. NRF2 mutations are exclusively found in the DLG and ETGE motifs responsible for binding to KEAP1.

Figure 5

Two strategies for cancer therapy focused on NRF2. (A) Chemoprevention against carcinogens by NRF2 inducers in normal cells. (B) Anticancer therapy against NRF2-addicted cancer cells by NRF2 inhibitors.