Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer

Abstract

The Keap1-Nrf2 signaling pathway is a major regulator of the cytoprotective response, participating in endogenous and exogenous stress caused by ROS (reactive oxygen species). Nrf2 is the core of this pathway. We summarized the literature on Keap1-Nrf2 signaling pathway and summarized the following three aspects: structure, function pathway, and cancer and clinical application status. This signaling pathway is similar to a double-edged sword: on the one hand, Nrf2 activity can protect cells from oxidative and electrophilic stress; on the other hand, increasing Nrf2 activity can enhance the survival and proliferation of cancer cells. Notably, oxidative stress is also considered a marker of cancer in humans. Keap1-Nrf2 signaling pathway, as a typical antioxidant stress pathway, is abnormal in a variety of human malignant tumor diseases (such as lung cancer, liver cancer, and thyroid cancer). In recent years, research on the Keap1-Nrf2 signaling pathway has become increasingly in-depth and detailed. Therefore, it is of great significance for cancer prevention and treatment to explore the molecular mechanism of the occurrence and development of this pathway.

Keywords: Keap1; Nrf2; cancer; clinical; function; prevention; structure; transcriptional regulation.

Figure 1

Structure and function of Keap1. (A) The protein structure of Keap1 and the functions of its domains. (B) The regulatory network of Keap1. Several microRNAs (miR-223, miR-200a, and miR-432-39) also affect Keap1 translation levels. The Keap1 protein is also regulated by various modifications (such as methylation, oxidation, glycosylation, and alkylation) after translation. At the same time, it is also affected by other factors (such as P62 and TRIM25) that regulate its expression.

Figure 2

Interaction between Keap1 and Nrf2. Under basic conditions, Keap1 binds to Nrf2 through ETGE and DLEG, and Nrf2 is polyadenylated by the cul3-based E3 ligase complex. This polygeneralization leads to the rapid degradation of Nrf2 by the proteasome. At the same time, a small amount of Nrf2 escapes from the inhibition complex and reaggregates in the nucleus, mediating the expression of basic ARE-dependent genes and thus maintaining intracellular homeostasis. When stimulated by the outside world (drugs, phytochemicals and devivates, environmental agents, and endogenous inducers), the inducer modifies Keap1 cysteine and inhibits Nrf2 ubiquitination by dissociating the inhibition complex. According to the hinge and latch model, the modification of specific Keap1 cysteine residues leads to the conformational change of Keap1, leading to the separation of the Nrf2 DLG motif from Keap1. The ubiquitination of Nrf2 is destroyed, but binding to the ETGE motif still occurs. At the same time, in another model (Keap1-Cul3 dissociation model), the binding of Keap1 and Cul3 is destroyed under the action of electrophilic reagents, which leads to the escape of Nrf2 from the ubiquitination system. In these two models of Keap1-Nrf2, both will induce modification and inactivate Keap1, which will bind Nrf2. Therefore, the newly synthesized Nrf2 protein bypasses Keap1 and enters the nucleus, binds to the antioxidant response element (ARE), and drives the expression of the Nrf2 target genes GCLC, GCLM, NQO1, HO-1, and GST. At the same time, it will also affect other processes (glutathione synthesis, antioxidant systems, PPP/NADPH synthesis, iron regulation, etc.).

Figure 3

Structure and function of Nrf2. (A) Schematic diagram of the Nrf2 protein structure. (B) Schematic diagram of the regulation of human Nrf2 gene expression. The control mechanism of nuclear factor erythroid 2p45 related factor 2 (Nrf2) gene expression. The Nrf2 gene is depicted as the bottom of a solid black horizontal line graph, and the red right angle arrow represents the transcription start site (TSS). Breast cancer protein (BRCA) 1 increases the expression of Nrf2, which is mediated by ARNT. Lipopolysaccharide (LPS), as a factor promoting inflammation, can induce Nrf2 to recruit TSS (kB2) from the p50–p65 heterodimer through the nuclear factor (NF)-kB binding site. In the process of tumorigenesis and development, Nrf2 can be activated by many factors (such as Jun or Myc). Fasting increases the mRNA expression level of Nrf2, which may be mediated by peroxisome proliferator activation (PPAR). Many miRNAs, such as miR-27a, miR-28, miR-93, miR-142-5p, miR-144, and miR-153, inhibit the expression of Nrf2.

Figure 4

Mechanisms for constitutive nuclear accumulation of Nrf2 in cancer. (A) Somatic mutations in Nrf2 or Keap1 disrupt the interaction of these two proteins. (B) Hypermethylation of the Keap1 promoter in lung cancer and prostate cancer leads to decreased expression of Keap1 mRNA, thereby increasing nuclear accumulation of Nrf2. (C) In familial papillary renal carcinoma, the loss of fumarate hydratase activity leads to the accumulation of fumarate, which in turn leads to the succination of the Keap1 cysteine residue (2SC). (D) The accumulation of interfering proteins such as p62 and p21 can interfere with the binding of Nrf2 to Keap1, leading to an increase in nuclear Nrf2.