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Review
. 2013 Oct 15;27(20):2179-91.
doi: 10.1101/gad.225680.113.

The emerging role of the Nrf2-Keap1 signaling pathway in cancer

Melba C Jaramillo  1 , Donna D Zhang
Affiliations
Review

The emerging role of the Nrf2-Keap1 signaling pathway in cancer

Melba C Jaramillo et al. Genes Dev. .

Abstract

The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.

Keywords: ARE; Keap1; Nrf2; chemoprevention; chemoresistance; oxidative stress.

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Figures

Figure 1.
Figure 1.
Conserved domains of Nrf2 and Keap1. (A) Nrf2 contains seven domains, known as Neh1–Neh7. The Neh2 domain contains two binding motifs, DLG and ETGE, which interact with Keap1. The Neh4, Neh5, and Neh3 domains are important for the transactivation activity of Nrf2. The Neh6 domain is a serine-rich region that regulates Nrf2 stability. The Neh1 domain is a basic region leucine zipper motif that is important for its stability, DNA binding, and dimerization with Maf. (B) Keap1 contains three major domains. The BTB domain mediates Keap1 homodimerization and associates with Cul3. The IVR domain contains critical cysteine residues and connects the BTB domain with the C terminus Kelch/DGR domain. The Kelch/DGR domain mediates binding with the Neh2 domain of Nrf2.
Figure 2.
Figure 2.
Schematic model of the Nrf2–Keap1 signaling pathway. Under basal conditions, Keap1 binds to the ETGE and DLG motifs on Nrf2 and brings Nrf2 into Keap1–Cul3–E3 ubiquitin ligase complex, leading to ubiquitination and subsequent degradation of Nrf2. Oxidative stress or electrophiles can cause a conformational change in the Keap1–Cul3–E3 ubiquitin ligase by acting on specific cysteine residues in Keap1. These changes disrupt Nrf2–Keap1 binding at the DLG domain. Nrf2 is stabilized, and free Nrf2 translocates to the nucleus, where it dimerizes with members of the small Maf family and binds to AREs (5′-RTGABNNNGCR-3′) within regulatory regions of a wide variety of cell defense genes, including NQO1, GCLM, HO-1, and MRP1. (E) ETGE; (D) DLG.
Figure 3.
Figure 3.
Cross-talk between Nrf2 and other proteins. The substrate adaptor sequestosome 1 protein (p62) modulates the Nrf2–Keap1 signaling pathway by directly interacting with Keap1. p62 sequesters Keap1 in autophagosomes, which results in a decrease in Nrf2 ubiquitination, an increase in Nrf2 stability, and activation of Nrf2 target genes. Nrf2 is stabilized in response to p21 up-regulation. p21 associates with the DLG motif on Nrf2, thereby disrupting the ability of Keap1 to properly bind and ubiquitinate Nrf2. DPP3 binds to Keap1, inhibits Nrf2 ubiquitination, and drives Nrf2-dependent transcription in cancer cells. (E) ETGE; (S) STGE; (D) DLG.
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