Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer

Abstract

Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors. However, NRF2/KEAP1 signaling pathway is dysregulated in various cancers, thus promoting tumor cell survival and metastasis. In the present review, we discuss the mechanisms of normal and deregulated NRF2 signaling pathway focusing on its cancer-related functions. We further explore activators and inhibitors of this pathway as cancer targeting drug candidates in order to provide an extensive background on the subject.

Keywords: Keap1; Nrf2; cancer; oxidative stress.

Figure 1

Schematic diagram is showing domain structures of nuclear factor E2-related factor 2 (NRF2), and Kelch-like ECH-associated protein 1 (KEAP1). (A) NRF2 has seven domains (Neh1-7). The Neh1 domain is responsible for DNA binding. The Neh2 domain contains DLG and ETGE motifs that are critical for KEAP1 binding. The Neh3, Neh4, and Neh5 are known transactivation domains. The Neh6 is important for proteasomal degradation of NRF2. The Neh7 domain is responsible for RXRα binding. (B) KEAP1 has five domains; NTR, CTR, BTB, Bric-a-Brac domain binds to Cul3 that is critical for KEAP1 dimerization; IVR, intervening region contains cysteine residues 273 (C273) and 288 (C288) that are important for sensing reactive oxygen species (ROS); the Kelch/DGR domain is important for NRF2 binding. BTB, Broad complex/Tramtrack/Bric-a-Brac; CTR, carboxy-terminal domain; Cul3, Cullin E3 ubiquitin ligase; IVR, Intervening region; Neh, NRF2-ECH homology; NTR, N-terminal region; RXRα, retinoid X receptor-alpha.

Figure 2

NRF2 activation in healthy and cancer cells. (A) In healthy cell, under normal conditions NRF2 level is inhibited by KEAP1-mediated proteasomal degradation; under stress conditions, NRF2 dissociates from KEAP1, accumulates in nucleus and activates cytoprotective gene expression. (B) In cancer cells, different molecular mechanisms cause constitutive NRF2 activation that results in drug resistance, stress adaptation, cells proliferation, and activation of metabolic reprogramming and induces expression of genes related to tumor progression. NRF2, nuclear factor erythroid 2-related factor 2; KEAP1, Kelch-like ECH-associated protein 1; MAF, small musculoaponeurotic fibrosarcoma protein; Pol II; RNA polymerase II; ARE: antioxidant response element.

Figure 3

Different molecular mechanisms are responsible for activation of NRF2-KEAP1 pathway in cancer; somatic mutations in KEAP1 or NRF2; epigenetic modifications in KEAP1 and NRF2 promoter; post-transcriptional activation of NRF2; oncogenic signals; hormonal activation.

Figure 4

Some NRF2 activator molecules. (a) Curcumin, (b) sulforaphane, (c) oltipraz, (d) carnosol, (e) resveratrol, and (f) oleanane.