Invited Review ArticleRole of chemopreventive phytochemicals in NRF2-mediated redox homeostasis in humans☆
Graphical abstract
Introduction
Through evolution, oxygen was selected as the terminal electron acceptor in the respiratory chain for energy production. It readily accepts the electrons generated during aerobic metabolism, producing reactive oxygen species (ROS), such as superoxide, as by-products [1]. For instance, uncoupling of mitochondrial electron transport can release ROS. Other cellular components also contribute to ROS production. These include plasma membrane-bound or neutrophil NADPH oxidase, endoplasmic reticulum-anchored cytochrome P450, xanthine oxidase, etc. [2]. Besides endogenous production of ROS formed during normal aerobic metabolism or oxidative burst in selected immune cells under acute inflammatory conditions, some redox-cycling xenobiotics and ionizing radiation provoke oxidative stress through ROS generation (Fig. 1). Superoxide anion (O2.-) produced by the one-electron reduction of molecular oxygen is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD) activity. Although hydrogen peroxide functions as an important messenger in the intracellular signaling network, it forms extremely reactive hydroxyl radical in the presence of transition metal ions. Alternatively, superoxide can react rapidly with nitric oxide to produce more reactive peroxynitrite [1]. Both hydroxyl radical and peroxynitrite can damage critical biomolecules, including DNA, protein and membrane lipid, thereby causing genotoxicity or disrupting cellular homeostasis. Therefore. ROS-induced oxidative stress is implicated in a wide spectrum of human disorders including cancer [3].
The susceptibility of cellular components to oxidative stress depends on the redox status, which is determined by the levels of ROS and local antioxidant defense capacity. Some endogenous antioxidant molecules, such as reduced glutathione (GSH) and α-lipoic acid, are abundant in cell environment. Antioxidant vitamins, such as ascorbic acid (Vit C) and tocopherol (Vit E) are also available for scavenging or inactivating ROS (Fig. 1). However, these ready-made endogenous antioxidants can be overwhelmed by excessive ROS production, and there is a need for more fundamental and dynamic antioxidant defense mechanism. A master switch of the cellular antioxidant signaling is the transcription factor, nuclear transcription factor erythroid 2-related factor 2 (NRF2) that plays a vital role in adaptive survival response to ROS-induced oxidative stress [4].
Under unstressed/physiologic conditions, NRF2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (KEAP1) that is a cytoskeleton binding protein. KEAP1 is a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. While bound to KEAP1, NRF2 undergoes ubiquitination by the KEAP1-Cul3 ubiquitin E3 ligase complex followed by rapid proteasomal degradation. The release of NRF2 from its repressor and subsequent translocation into nucleus are considered to be achieved by alterations in the structure of KEAP1. Of note, electrophilic or oxidative stresses covalently modify or oxidize, respectively the sensor cysteine residues of KEAP1. This results in a decline in the E3 ligase activity and concurrent stabilization of NRF2 [5]. NRF2, once migrated to the nucleus, binds to the antioxidant response elements (ARE) or electrophile response element (EpRE) present in the promoter region of target genes, many of which encode antioxidant enzymes and other cytoprotective proteins. These include heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase (NQO1), glutamate-cysteine ligase (GCL), glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) as listed in Fig. 1. This physiologically important stress response has been known to be also activated/potentiated by some chemopreventive and cytoprotective phytochemicals [6].
It is now evident that the extent and duration of the ROS-induced oxidative stress as well as the intracellular redox milieu differentially contribute to non-lethal cellular damage, cell death, or tumor development and progression [7]. Thus, ROS can cause either cancer initiating DNA damage/genomic instability or apoptotic/necrotic/autophagic cell death, depending on the severity of oxidative stress it provokes as well as intracellular redox environment. NRF2 plays a central role in body's defense mechanisms whereby a diverse array of toxic prooxidants and other reactive species (e.g. electrophiles and reactive nitrogen species) can be neutralized or eliminated before they damage genomic DNA or kill cells [8].
NRF2 regulates cellular redox homeostasis and protects normal cells from oxidative death as well as genotoxic insult. In cancer cells, however, the threshold of ROS is generally higher than that in normal cells. To overcome the excessive ROS-mediated oxidative stress, cancer cells tend to be addicted to the NRF2-mediated antioxidant defense signaling pathways [9]. Constitutive hyperactivation of NRF2 in cancer cells creates a more reductive tumor microenvironment that favors their survival over robust oxidative stress caused by redox active chemotherapeutics or radiotherapy [[10], [11], [12]]. NRF2 also upregulates the expression of some multidrug resistance family proteins, responsible for cancer cell survival and tolerance to the chemo- and radiotherapy [13,14].
This review focuses on chemopreventive or cytoprotective activities of selected NRF2 activating phytochemicals evaluated in human intervention trials or in human cells, and underlying mechanisms. Their effects on cancer cell growth and progression are also summarized.
Section snippets
Mechanisms of NRF2 activation by chemopreventive and cytoprotective phytochemicals
The level of NRF2 protein expression is relatively low in normal conditions. NRF2 activity is tightly regulated at the transcriptional/translational/post-translational levels and also through epigenetic modulations (Fig. 2) [15].
Chemopreventive phytochemicals with NRF2 activating/inducing activities in humans and human cells
Phytochemicals are chemical substances derived from plants, most of which are generated as secondary metabolites [65,66]. Although the nutritional value is relatively low, many of them exert diverse pharmacologic effects. Multiple lines of evidence support that phytochemicals derived from fruits, vegetables, herbs, spice, and grains have capabilities to inhibit, retard, or reverse the multistage carcinogenesis through distinct mechanisms [6,67].
Oxidative stress is closely linked to
Effects of NRF2 activating phytochemicals on cancer cell proliferation and survival
In general, elevated levels of ROS have been detected in cancer cells compared with normal cells [174]. Such unique redox environment of cancer cells renders them more sensitive to ROS-manipulation strategies [175]. The inhibition of antioxidant enzyme activity/expression can augment ROS production, which often triggers apoptosis in cancer cells. Several studies have demonstrated that the blockage of the antioxidant system results in the induction of ROS-mediated cytotoxicity in cancer cells [
Concluding remarks
Formation of ROS together with a concomitant fall in the body's intrinsic antioxidant capacity results in a state of oxidative stress, which contributes to carcinogenesis. Physiologically, ROS formed as by-products of aerobic metabolism are often utilized as a second messenger to execute normal cellular functions in response to growth factors, hormones, and neurotransmitters. However, high levels of ROS generated by external stimuli including chemical carcinogens, ultraviolet radiation,
Acknowledgements
This study was supported by the Basic Science Research Program grant (No. 2021R1A2C2014186 to Y.-J. S; No. 2020R1A2C1103139 to D.-H. K.; No. 2020R1l1A3066367 to K.-S. C.) from the National Research Foundation (NRF) of the Republic of Korea.
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This is part of a Special Issue - The effects of diet on human in vivo redox state
Guest Editors: Dana R. Crawford, Young Joon Surh
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These authors equally contributed to this work.