Role of the Keap1–Nrf2 Pathway in Cancer

doi:10.1016/B978-0-12-420117-0.00008-6

Advances in Cancer Research

Volume 122, 2014, Pages 281-320

https://doi.org/10.1016/B978-0-12-420117-0.00008-6 Get rights and content

Abstract

The Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor E2-related factor 2 (Nrf2) pathway is one of the major signaling cascades involved in cell defense and survival against endogenous and exogenous stress. While Nrf2 and its target genes provide protection against various age-related diseases including tumorigenesis, constitutively active Nrf2 in cancer cells increases the expression of cytoprotective genes and, consequently, enhances proliferation via metabolic reprogramming and inhibition of apoptosis. Herein, we review the current understanding of the regulation of Nrf2 in normal cells as well as its dual role in cancer. Furthermore, the mechanisms of Nrf2 dysregulation in cancer, consequences of unchecked Nrf2 activity, and therapies targeting the Keap1–Nrf2 system are discussed.

Introduction

Oxidative stress, an imbalance between the production and disposal of reactive oxygen species (ROS), plays an important role in various diseases including cancer (Valko et al., 2007). The Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor E2-related factor 2 (Nrf2) pathway is one of the most important signaling cascades involved in cell defense and survival against xenobiotics and oxidative stress. Nrf2 protects against the development of several diseases, such as cancer and neurodegenerative diseases (Hybertson et al., 2011, Ma and He, 2012), and various activators of the Keap1–Nrf2 pathway have been extensively studied for chemoprevention (Zhao, Gao, & Qu, 2010). Recently, it has become evident that Nrf2 has a protective role not only in normal cells but also in cancer cells, in which aberrant signaling via the Keap1-Nrf2 pathway leads to constitutive activation of Nrf2 and upregulation of target genes resulting in enhanced cancer cell survival. (Padmanabhan et al., 2006, Shibata, Kokubu, et al., 2008, Wang, Sun, Villeneuve, et al., 2008). In this chapter, we will summarize the current knowledge on the regulation of Nrf2 in normal cells as well as the mechanisms of dysregulation in cancer. In addition, we will discuss the clinical ramifications of Nrf2 overactivity and how the Keap1–Nrf2 system can be targeted in cancer therapy.

Section snippets

The Keap1–Nrf2 Pathway

Cells have evolved highly efficient protective mechanisms that enable their survival under conditions of stress. One of the major cytoprotective signaling cascades is the Keap1–Nrf2 pathway, which is activated in response to endogenous or exogenous stress. Under basal conditions, Nrf2 is bound to its cytosolic inhibitor Keap1, which functions as an adaptor protein in the cullin 3 (Cul3)-based E3 ligase complex that ubiquitinates Nrf2 resulting in proteasomal degradation (Kobayashi et al., 2004

The role of oxidative stress in cancer

Oxidative stress plays an important role in carcinogenesis (Valko et al., 2007). Reactive oxygen species (ROS) are involved in both the initiation and progression of cancer and are generated by cancer cells via increased mitochondrial activity and accelerated metabolism needed for tumor growth and cellular proliferation (Hanahan and Weinberg, 2011, Storz, 2005, Szatrowski and Nathan, 1991, Valko et al., 2007). ROS can cause mutations in DNA, including sugar and base modifications, single- or

Nrf2 as a prognostic marker of cancer

Inasmuch as patients with overactive Nrf2 usually have chemo- and radioresistance and poor prognosis, Nrf2 expression could be used as a novel biomarker for personalized molecular therapies. In addition to analyzing mutations of NFE2L2, KEAP1, or other factors involved in the signaling pathway, other markers, such as KEAP1 promoter methylation, Nrf2 protein, or the expression of its target genes, could be analyzed, as the mechanisms of Nrf2 overactivity are diverse. However, while the

Concluding Remarks and Future Perspectives

Within the past few years, it has become evident that Nrf2 not only plays a role in prevention of malignant transformation in healthy tissues but also is important for protecting cancer cells from chemotherapy and radiotherapy and facilitating cancer growth via, for example, metabolic reprogramming. Just as large-scale genomics endeavors like the TCGA project have revolutionized cancer research, they have provided important insights into the dysregulation of the Keap1–Nrf2 pathway in cancer. As

Acknowledgments

This work was supported by the Academy of Finland, the Sigrid Juselius Foundation, Finnish Cultural Organization, Emil Aaltonen Foundation, and the Finnish Cancer Organisations.

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The Keap1-Nrf2 signalling to transcriptionally regulate antioxidant response element (ARE)-driven target genes has been accepted as key redox-sensitive pathway governing a vast variety of cellular stresses during healthy survival and disease development. Herein, we identified two nuanced isoforms α and β of Keap1 in HepG2 cells, arising from its first and another in-frame translation starting codons, respectively. In identifying those differential expression genes monitored by Keap1α and/or Keap1β, an unusual interaction of Keap1 with Smad2/3 was discovered by parsing transcriptome sequencing, Keap1-interacting protein profiling and relevant immunoprecipitation data. Further examination validated that Smad2/3 enable physical interaction with Keap1, as well as its isoforms α and β, by both EDGETSD and DLG motifs in the linker regions between their MH1 and MH2 domains, such that the stability of Smad2/3 and transcriptional activity are enhanced with their prolonged half-lives and relevant signalling responses from the cytoplasmic to nuclear compartments. The activation of Smad2/3 by Keap1, Keap1α or Keap1β was much likely contributable to a coordinative or another competitive effect of Nrf2, particularly in distinct Keap1-based cellular responses to its cognate growth factor (i.e. TGF-β1) or redox stress (e.g. stimulated by tBHQ and DTT). Overall, this discovery presents a novel functional bridge crossing the Keap1-Nrf2 redox signalling and the TGF-β1-Smad2/3 pathways so as to coordinately regulate the healthy growth and development.
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Alterations in complex cellular phenotype each typically involve multistep activation of an ultrasensitive molecular switch (e.g., to adaptively initiate an apoptosis, inflammasome, Nrf2-ARE anti-oxidant, or heat-shock activation pathway) that triggers expression of a suite of target genes while efficiently limiting false-positive switching from a baseline state. Such switches exhibit nonlinear signal-activation relationships. In contrast, a linear no-threshold (LNT) dose-response relationship is expected for damage that accumulates in proportion to dose, as hypothesized for increased risk of cancer in relation to genotoxic dose according to the multistage somatic mutation/clonal-expansion theory of cancer, e.g., as represented in the Moolgavkar-Venzon-Knudsen (MVK) cancer model by a doubly stochastic nonhomogeneous Poisson process. Mesothelioma and lung cancer induced by exposure to carcinogenic (e.g., certain asbestos) fibers in humans and experimental animals are thought to involve modes of action driven by mutations, cytotoxicity-associated inflammation, or both, rendering ambiguous expectations concerning the nature of model-implied shape of the low-dose response for above-background increase in risk of incurring these endpoints. A recent Inflammation Somatic Mutation (ISM) theory of cancer posits instead that tissue-damage-associated inflammation that epigenetically recruits, activates and orchestrates stem cells to engage in tissue repair does not merely promote cancer, but rather is a requisite co-initiator (acting together with as few as two somatic mutations) of the most efficient pathway to any type of cancer in any reparable tissue (Dose-Response 2019; 17(2):1–12). This theory is reviewed, implications of this theory are discussed in relation to mesothelioma and lung cancer associated with chronic asbestos inhalation, one of the two types of ISM-required mutations is here hypothesized to block or impede inflammation resolution (e.g., by doing so for GPCR-mediated signal transduction by one or more endogenous autacoid specialized pro-resolving mediators or SPMs), and supporting evidence for this hypothesis is discussed.
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Chapter Eight - Role of the Keap1–Nrf2 Pathway in Cancer

Abstract

Introduction

Section snippets

The Keap1–Nrf2 Pathway

The role of oxidative stress in cancer

Nrf2 as a prognostic marker of cancer

Concluding Remarks and Future Perspectives

Acknowledgments

Cancer Cell

Toxicology In Vitro: An International Journal Published in Association with BIBRA

Toxicology and Applied Pharmacology

Biochimica et Biophysica Acta

The Journal of Biological Chemistry

The Journal of Nutrition

The Journal of Biological Chemistry

Mutation Research

Molecular Cell

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Toxicology Letters

Free Radical Biology and Medicine

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Free Radical Biology & Medicine

Cell

Cancer Letters

Trends in Biochemical Sciences

The Journal of Biological Chemistry

Molecular Aspects of Medicine

Molecular Cell

Biochemical and Biophysical Research Communications

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Free Radical Biology & Medicine

The Journal of Pathology

Journal of Proteomics

Current Opinion in Plant Biology

Toxicology and Applied Pharmacology

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Free Radical Biology & Medicine

Food and Chemical Toxicology

Integrative radiogenomic profiling of squamous cell lung cancer

Cancer Research

The Bcl-2 apoptotic switch in cancer development and therapy

Oncogene

The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis

International Journal of Molecular Medicine

Aberrant Keap1 methylation in breast cancer and association with clinicopathological features

Epigenetics: Official Journal of the DNA Methylation Society

The role of mitochondria in ageing and carcinogenesis

Clinical and Experimental Dermatology

p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death

The Journal of Cell Biology

The engine driving the ship: Metabolic steering of cell proliferation and death

Nature Reviews. Molecular Cell Biology

The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation

Oncogene

Comprehensive genomic characterization of squamous cell lung cancers

Nature

The angiogenic switch in carcinogenesis

Seminars in Cancer Biology

Reactive oxygen species in apoptosis induced by cisplatin: Review of physiopathological mechanisms in animal models

European Archives of Oto-Rhino-Laryngology: Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): Affiliated with the German Society for Oto-Rhino-Laryngology—Head and Neck Surgery

Nrf2 defends the lung from oxidative stress

Antioxidants & Redox Signaling

Identification of novel NRF2-regulated genes by ChIP-Seq: Influence on retinoid X receptor alpha

Nucleic Acids Research

Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

Oncogene

The PI3K pathway as drug target in human cancer

Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology

Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival

Molecular and Cellular Biology