Cancer Chemoprevention Mechanisms Mediated Through the Keap1–Nrf2 Pathway

Abstract

The cap'n'collar (CNC) bZIP transcription factor Nrf2 controls expression of genes for antioxidant enzymes, metal-binding proteins, drug-metabolising enzymes, drug transporters, and molecular chaperones. Many chemicals that protect against carcinogenesis induce Nrf2-target genes. These compounds are all thiol-reactive and stimulate an adaptive response to redox stress in cells. Such agents induce the expression of genes that posses an antioxidant response element (ARE) in their regulatory regions. Under normal homeostatic conditions, Nrf2 activity is restricted through a Keap1-dependent ubiquitylation by Cul3-Rbx1, which targets the CNC-bZIP transcription factor for proteasomal degradation. However, as the substrate adaptor function of Keap1 is redox-sensitive, Nrf2 protein evades ubiquitylation by Cul3-Rbx1 when cells are treated with chemopreventive agents. As a consequence, Nrf2 accumulates in the nucleus where it heterodimerizes with small Maf proteins and transactivates genes regulated through an ARE. In this review, we describe synthetic compounds and phytochemicals from edible plants that induce Nrf2-target genes. We also discuss evidence for the existence of different classes of ARE (a 16-bp 5'-TMAnnRTGABnnnGCR-3' versus an 11-bp 5'-RTGABnnnGCR-3', with or without the embedded activator protein 1-binding site 5'-TGASTCA-3'), species differences in the ARE-gene battery, and the identity of critical Cys residues in Keap1 required for de-repression of Nrf2 by chemopreventive agents.

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

“…TBE-31, via induction of the Keap1/Nrf2/ARE pathway, protects against oxidative stress caused by the combination of UVA radiation and 6-TG The Keap1/Nrf2/ARE pathway controls the gene expression of a large network of cytoprotective proteins, including antioxidant enzymes (3)(4)(5)(6). Because oxidative stress represents one of the initial events contributing to the increased photosensitivity and skin cancer risk under conditions of thiopurine treatment, we hypothesized that the protective effects of the Keap1/Nrf2/ARE pathway may extend beyond reduction of 6-TG incorporation in DNA.…”

“…Under basal conditions, this pathway does not operate at its maximal capacity but is highly inducible by various stress stimuli and also by small molecules, all of which have the ability to react with sulfhydryl groups (1,2). Inducers react with specific cysteine residues of the protein sensor Kelch-like ECH-associated protein 1 (Keap1) which loses its ability to target transcription factor NF-E2-related factor 2 (Nrf2) for ubiquitination and proteasomal degradation, resulting in stabilization of Nrf2, binding to the antioxidant response element (ARE) and transcriptional activation of cytoprotective genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), heme oxygenase 1, thioredoxin reductase, aldo-keto reductases (3)(4)(5)(6). Inducers are also antiinflammatory agents, and there is a linear correlation between these two biologic activities that spans 6 orders of magnitude of inducer concentrations (7,8).…”

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

“…Nrf2 plays an essential role in regulating cellular redox homeostasis and protects cells from oxidative stress by activating transcription of its target genes (Jaiswal, 2004) and enhancing cellular defense systems such as antioxidant and phase II detoxifying enzymes (Hayes et al, 2010;Kaspar et al, 2009). Because oxidative stress is implicated in the initiation and progression of cancer, activation of Nrf2 signaling has been considered as an useful strategy for chemoprevention (Giudice et al, 2010).…”

Inflammatory Macrophages Induce Nrf2 Transcription Factor-dependent Proteasome Activity in Colonic NCM460 Cells and Thereby Confer Anti-apoptotic Protection

“…This protection includes the potential of Nrf2-induced phase II enzyme expression to prevent genotoxic insults from oxidative stress, thus making Nrf2 activation a promising tool in chemo prevention of cancer (6). Electrophils and anti-oxidants such as tert-butylhydroquinone (tBHQ) and the phytochemical sulforaphane are well known to induce Nrf2 and thereby to stimulate phase II enzyme expression.…”

“…Electrophils and anti-oxidants such as tert-butylhydroquinone (tBHQ) and the phytochemical sulforaphane are well known to induce Nrf2 and thereby to stimulate phase II enzyme expression. Thus, Nrf2 inducing agents have been suggested to be of substantial benefit in cancer prevention (5,6,9 However, evidence accumulates that Nrf2 can also promote tumorigenesis (10 -13) and resistance of tumors to chemotherapy, e.g. by inducing detoxification of anti-cancer drugs in a phase II-dependent fashion (14 -16).…”