Elsevier

Free Radical Biology and Medicine

Volume 172, 20 August 2021, Pages 699-715
Free Radical Biology and Medicine

Invited Review Article
Role of chemopreventive phytochemicals in NRF2-mediated redox homeostasis in humans

https://doi.org/10.1016/j.freeradbiomed.2021.06.031Get rights and content

Highlights

  • NRF2, a master switch of antioxidant signaling, plays a vital role in adaptive survival response to oxidative stress.

  • NRF2 activity is regulated at the transcriptional/translational/post-translational levels and also epigenetically.

  • Many phytochemicals exert cancer chemopreventive and cytoprotective effects through activation of NRF2 signaling.

Abstract

While functioning as a second messenger in the intracellular signaling, ROS can cause oxidative stress when produced in excess or not neutralized/eliminated properly. Excessive ROS production is implicated in multi-stage carcinogenesis. Our body is equipped with a defense system to cope with constant oxidative stress caused by the external insults, including redox-cycling chemicals, radiation, and microbial infection as well as endogenously generated ROS. The transcription factor, nuclear transcription factor erythroid 2-related factor 2 (NRF2) is a master switch in the cellular antioxidant signaling and plays a vital role in adaptive survival response to ROS-induced oxidative stress. Although NRF2 is transiently activated when cellular redox balance is challenged, this can be overwhelmed by massive oxidative stress. Therefore, it is necessary to maintain the NRF2-mediated antioxidant defense capacity at an optimal level. This review summarizes the natural NRF2 inducers/activators, especially those present in the plant-based diet, in relation to their cancer chemopreventive potential in humans. The molecular mechanisms underlying their stabilization or activation of NRF2 are also discussed.

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.

References (209)

  • D. Martin et al.

    Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol

    J. Biol. Chem.

    (2004)
  • M. Salazar et al.

    Glycogen synthase kinase-3β inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2

    J. Biol. Chem.

    (2006)
  • A.I. Rojo et al.

    Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: role of glycogen synthase kinase-3

    Free Radic. Biol. Med.

    (2012)
  • O.H. Lee et al.

    An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance

    J. Biol. Chem.

    (2007)
  • M. Montgomery et al.

    Epigenetic gene regulation by dietary compounds in cancer prevention

    Adv. Nutr.

    (2019)
  • J.H. Lee et al.

    Dietary phytochemicals and cancer prevention: nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

    Pharmacol. Ther.

    (2013)
  • C. Zhang et al.

    Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation

    Biochem. Pharmacol.

    (2013)
  • T.O. Khor et al.

    Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation

    Biochem. Pharmacol.

    (2011)
  • S. Li et al.

    Pelargonidin reduces the TPA induced transformation of mouse epidermal cells-potential involvement of Nrf2 promoter demethylation

    Chem. Biol. Interact.

    (2019)
  • H. Kim et al.

    Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells

    J. Nutr. Biochem.

    (2016)
  • R.J. Molyneux et al.

    Phytochemicals: the good, the bad and the ugly?

    Phytochemistry

    (2007)
  • K.S. Chun et al.

    Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals

    Toxicol. Lett.

    (2014)
  • C.R. Zhao et al.

    Nrf2-ARE signaling pathway and natural products for cancer chemoprevention

    Cancer Epidemiol

    (2010)
  • W. Li et al.

    Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis

    Biochem. Pharmacol.

    (2008)
  • S.A. Rushworth et al.

    The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance

    Blood

    (2012)
  • J.V. Higdon et al.

    Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

    Pharmacol. Res.

    (2007)
  • M.H. Traka et al.

    Transcriptional changes in prostate of men on active surveillance after a 12-mo glucoraphanin-rich broccoli intervention-results from the Effect of Sulforaphane on prostate CAncer PrEvention (ESCAPE) randomized controlled trial

    Am. J. Clin. Nutr.

    (2019)
  • R.L. Auten et al.

    Oxygen toxicity and reactive oxygen species: the devil is in the details

    Pediatr. Res.

    (2009)
  • W. Dröge

    Free radicals in the physiological control of cell function

    Physiol. Rev.

    (2002)
  • B.C. Dickinson et al.

    Chemistry and biology of reactive oxygen species in signaling or stress responses

    Nat. Chem. Biol.

    (2011)
  • Y.J. Surh

    Nrf2, an essential component of cellular stress response, as a potential target of hormetic phytochemicals

    J. Food Drug Anal.

    (2012)
  • T. Unoki et al.

    Nrf2 activation and its coordination with the protective defense systems in response to electrophilic stress

    Int. J. Mol. Sci.

    (2020)
  • Y.J. Surh et al.

    Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals

    Planta Med.

    (2008)
  • M. Sova et al.

    Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review

    Drug Des. Dev. Ther.

    (2018)
  • Q. Ma

    Role of nrf2 in oxidative stress and toxicity

    Annu. Rev. Pharmacol. Toxicol.

    (2013)
  • H. Kitamura et al.

    NRF2 addiction in cancer cells

    Canc. Sci.

    (2018)
  • M. Xiang et al.

    Nrf2: bane or blessing in cancer?

    J. Canc. Res. Clin. Oncol.

    (2014)
  • M.C. Jaramillo et al.

    The emerging role of the Nrf2-KEPA1 signaling pathway in cancer

    Genes Dev.

    (2013)
  • V. Vollrath et al.

    Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene

    Biochem. J.

    (2006)
  • L.E. Tebay et al.

    Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease

    Free Radic. Biol. Med.

    (2018)
  • M. Yamamoto et al.

    The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis

    Physiol. Rev.

    (2018)
  • S. Dayalan Naidu et al.

    KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease

    Open Biol

    (2020)
  • C. Hu et al.

    Modification of Keap1 cysteine residues by sulforaphane

    Chem. Res. Toxicol.

    (2011)
  • M. Komatsu et al.

    The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

    Nat. Cell Biol.

    (2010)
  • A. Lau et al.

    A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62

    Mol. Cell Biol.

    (2010)
  • J.Y. Park et al.

    Curcumin activates Nrf2 through PKCδ-mediated p62 phosphorylation at Ser 351

    Sci. Rep.

    (2021)
  • C.M. Clements et al.

    DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • R. Li et al.

    Regulation of Nrf2 signaling

    React. Oxyg. Species

    (2019)
  • K.K.S. Narasimhan et al.

    Morinda citrifolia and its active principle scopoletin mitigate protein aggregation and neuronal apoptosis through augmenting the DJ-1/Nrf2/ARE signaling pathway

    Oxid. Med. Cell. Longev.

    (2019)
  • Y. Bai et al.

    Sulforaphane protects against cardiovascular disease via Nrf2 activation

    Oxid. Med. Cell. Longev.

    (2015)
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