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REVIEW
NF-
j
B and Nrf2 as prime molecular targets for chemopreventionand cytoprotection with anti-inflammatory and antioxidantphytochemicals
Young-Joon Surh
Æ
Hye-Kyung Na
Published online: 28 November 2007
Ó
Springer-Verlag 2007
Chemoprevention with dietary phytochemicals
Cancer is a multifactorial heterogeneous disease character-ized by multistage nature of pathogenesis. Over the past twoor three decades, we have witnessed an enormous progressin the development of a vast variety of anticancer drugs andstrategies. Nonetheless, we do not have magic bullets thatcan completely and selectively destroy malignant cells.Since neoplastic transformation, in general, is a relativelylengthy process that may take more than decades, there areample opportunities to intervene in the pathogenesis of cancer, especially at early phases of oncogenesis. One suchstrategy is chemoprevention, an attempt to use either natu-rally occurring or synthetic substances, or their mixtures, toblock, retard or even reverse the process of carcinogenesis.Numerous substances present in our daily diet, includingfruits, vegetables, grains, spices, and seeds, have beenshown to be effective in preventing cancer. Besides anti-oxidants, many plant-based organic chemical components,collectively called phytochemicals, retain pronouncedchemopreventive potential. Currently, a series of humanintervention trials are being considered with individualphytochemicals or their combination with known syntheticchemopreventive agents. However, precise assessment of underlying mechanisms of individual components is nec-essary before undertaking large-scale human trials.The chemopreventive effects that most edible phyto-chemicals exert are likely to be the sum of several distinctmechanisms. These include blockage of metabolic activa-tion and/or DNA binding of carcinogens, stimulation of detoxification, repair of DNA damage, suppression of cellproliferation and metastasis or angiogenesis, induction of differentiation or apoptosis of precancerous or maliganantcells, etc. [1]. Given the great structural diversity of phy-tochemicals, it is not feasible to define structure–activityrelationships or any other commonalities to deduce theirunderlying molecular mechanisms. In this context, one of the promising approaches employed in studying themechanisms of chemopreventive phytochemicals includesassessment of their effects on the specific components of signal transduction network that becomes often deregu-lated—either amplified or repressed—in many cancerousor transformed cells.It has been known that a wide array of dietary phyto-chemicals act on the human genome, either directly orindirectly, to alter specific gene expression, thereby influ-encing the overall carcinogenic processes. Recently, muchattention is being focussed on a new wave of nutritionresearch called ‘‘nutrigenomics’’. Nutrigenomics (or nu-tragenetics) can help understand how diseases such ascancer can be induced/aggravated or alleviated with dietarycomponents by modulating specific gene expression.Nutrigenomic approaches are also applicable for the cancerchemoprevention studies.
Signal transduction pathway mediating inflammationand redox signaling:NF-
j
B and Nrf2 as key player
In elucidating molecular mechanisms underlying chemo-preventive or chemoprotective actions of dietary phyto-chemicals, components of signal transduction pathwayshave been often considered as potential targets. Since the
Y.-J. Surh (
&
)
Á
H.-K. NaNational Research Laboratory of Molecular Carcinogenesisand Chemoprevention, College of Pharmacy,Seoul National University, Shinlim-dong,Kwanak-ku, Seoul 151-742, Republic of Koreae-mail: surh@plaza.snu.ac.kr
 123
Genes Nutr (2008) 2:313–317DOI 10.1007/s12263-007-0063-0
 
cellular signaling network often goes awry in carcinogen-esis, it is fairly rational and pragmatic to target intracellularsignaling cascades for achieving chemoprevention [1].Numerous molecules and events are involved in relayingintracellular signals. Both external and endogenous stimuliturn on or switch off critical events of this relay, therebytransmitting proper signaling to diverse downstream targetmolecules in a highly sophisticated fashion for fine-tuningof cellular homeostasis. Components of upstream or cyto-plasmic signaling networks include protein kinases, such asthe family of proline-directed serine/threonine kinasesnamed mitogen-activated protein kinases (MAPKs), pro-tein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K),protein kinase B/Akt, glycogen synthase kinase, etc.A new horizon in chemoprevention research is therecent discovery of molecular links between inflammationand cancer [2]. Modulation of cellular signaling involvedin chronic inflammatory response by anti-inflammatoryagents hence represents an important strategy in moleculartarget-based chemoprevention and cytoprotection [3].Components of the cell signaling network, especially thosewhich converge on the ubiquitous eukaryotic redox-sensi-tive transcription factor nuclear factor-kappaB (NF-
j
B),have been implicated in pathogenesis of many inflam-mation-associated disorders. Under normal physiologicconditions, NF-
j
B is sequestered in the cytoplasm bybinding to the inhibitory protein called I
j
B
a
. Phosphory-lation and subsequent ubiquitination results in degradationof I
j
B
a
by proteasomes (Fig.1). Phosphorylation of I
j
B
a
is mainly mediated by the I
j
B kinase (IKK) complex.Phosphorylation of specific serine residues of p65 subunitof NF-
j
B has been considered to facilitate the translocationof NF-
j
B to nucleus and interaction with the coactivatorCBP/p300.Induction of phase-2 detoxifying or antioxidant genesrepresents an important cellular defence in response tooxidative and electrophilic insults. Nuclear transcriptionfactor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) playsa crucial role in regulating phase-2 detoxifying/antioxidantgene induction. Like NF-
j
B, Nrf2 is present in the cyto-plasm as an inactive complex with the inhibitory proteinsubunit, in this case Keap1. Dissociation of Nrf2 fromKeap1 is prerequisite for nuclear translocation and sub-sequent transactivational activity. Once translocated intonucleus, Nrf2 interacts with a small Maf protein, forming aheterodimer that binds to antioxidant responsive elements(ARE) or electrophile responsive elements (EpRE) presentin the promoter/enhancer regions of genes encoding manyantioxidant and detoxifying enzymes (Fig.2). Keap1 con-tains several cysteine residues that function as sensorsof redox changes. Oxidation or covalent modification of these critical cysteine thiols diminishes the affinity of Nrf2for Keap1, releasing Nrf2 for nuclear translocation.Dissociation of the Nrf2-Keap1 complex is also assumed tobe stimulated through the phosphorylation of Nrf2 bydistinct upstream kinases such as MAPKs, PKC, PI3K, etc.As in the case of NF-
j
B, phosphorylation of Nrf2 is alsoconsidered to facilitate the interaction of this redox-sensi-tive transcription factor with CBP/p300. Many antioxidantsderived from dietary and medicinal plants have been foundto modulate Nrf2-Keap1 signaling, thereby potentiatingcellular antioxidant capacity or facilitating detoxification of carcinogens and other toxicants [4,5]. It is noteworthy that there is a good correlation between anti-inflammatoryactivity of some chemopreventive/cytoprotective agentsand their ability to induce antioxidant gene expression [6].In this context, it is interesting to note that Nrf2 plays a rolein protecting cells from not only oxidative stress but also
Fig. 1
Regulation of NF-
j
B activation by cellular signaling mole-cules. Upon stimulation of cells, activation of protein kinases such asphosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), c-JunNH
2
-terminal kinase (JNK), and extracellular signal-regulated kinase(ERK) induce phosphorylation of IKK 
a
 / 
b
. I
j
B
a
is rapidly phosphor-ylated by IKK 
a
 / 
b
and degraded via the ubiquitin-proteasomepathway. The resulting free NF-
j
B dimer (p50-p65) translocates tothe nucleus for the transcriptional regulation of multiple target genes.Some of the aforementioned proteine kinases may also catalyze thephosphorylation of p65 subunit of NF-
j
B, facilitating the nucleartranslocation and/or interaction with the coactivator CBP/p300.Chemopreventive phytochemicals can inhibit phosphorylation and/ or ubiquitination of I
j
B
a
or phosphorylation of p65 induced byseveral oncogenic stimuli, thereby hampering the nuclear transloca-tion and DNA binding of NF-
j
B. The cysteine residues presentin IKK 
a
 / 
b
are critical for catalytic activity and can be oxidizedby prooxidants or covalent modified by electrophiles, leading toinactivation of the enzyme. Some dietary phytochemicals or theirmetabolites can act as prooxidants capable of directly oxidizingcysteine thiol or indirectly by altering cellular redox status andsubsequently releasing ROS. Other groups of chemopreventivephytochemicals, especially those capable of acting as Michaelreaction acceptors, are electrophilic per se and can hence directlymodify the cysteine residues of IKK. Similar thiol modification byelectrophilic phytochemicals was also found to occur for the p50subunit of NF-
j
B[30], but this event is not included in this illustration to avoid complexity314 Genes Nutr (2008) 2:313–317
 123
 
inflammatory insult [7–12]. The possible cross-talk  between NF-
j
B sinaling and that mediated by Nrf2 meritsfurther investigation.
Chemopreventive phytochemicals targeting NF-
j
Band Nrf2
The current research in our laboratory concerns evaluationof various chemopreventive effects of some edible anti-oxidative and anti-inflammatory phytochemicals andelucidation of their underlying molecular mechanisms. Ourresearch program has attempted to unravel common eventsmediated by redox-sensitive transcription factors suchas NF-
j
B and Nrf2 and upstream kinases involved inthe cellular signaling network for molecular target-basedchemoprevention with selected dietary and medicinalphytochemicals, especially those with anti-inflammatoryand/or antioxidative properties [1].Curcumin, a yellow coloring agent contained in turmeric(
Curcuma longa
L., Zingiberaceae), has been reported topossess strong anti-tumor promotional as well as anti-inflammatory and antioxidant activities. Our recent studieshave demonstrated that curcumin inhibits expression of cyclooxygenase-2 (COX-2) in mouse skin treated with thetumor promoter 12-
O
-tetradecanoylphorbol-13-acetate(TPA) through inactivation of the eukaryotic transcriptionfactor NF-
j
B. Inhibition of NF-
j
B by curcumin appears tobe mediated by blocking ERK1/2 and p38 MAPK [13].Oral administration of curcumin also inhibits azoxyme-thane-initiated and dextran sulfate sodium (DSS)-promotedcolorectal carcinogenesis in mice (H.-S. Kim and Y.-J.Surh, manuscript in preparation).[6]-Gingerol, a pungent ingredient present in ginger(
 Zingiber officinale
Roscoe, Zingiberaceae), inhibitedTPA-induced tumor necrosis factor-alpha production,ornithine decarboxylase activity and skin tumor promotionin female ICR mice [14]. Topically applied [6]-gingerolinhibited TPA-induced phosphorylation of p65 at Ser 536and its interaction with the coactivator cAMP responseelement binding protein-binding protein (CBP/p300) inmouse skin, thereby rendering NF-
j
B transcriptionallyinactive [15]. The NF-
j
B inhibitory effects of [6]-gingerolappears to be associated with inhibition of p38 MAPK. [6]-Gingerol also inhibited anchorage-independent growth of mouse epidermal JB-6 cells stimulated with epidermalgrowth factor [16]. More recently, [6]-gingerol has beenshown to inhibit UVB-induced activation of NF-
j
B andCOX-2 expression in hairless mouse skin and also in animmortalized human keratinocytes cell line [17].Capsaicin, a major pungent principle of hot chili pepper(
Capsicum annuum
L., Solanaceae) with potential anti-inflammatory and anti-tumor promoting properties, alsosuppressed TPA-induced activation of NF-
j
B in mouseskin in vivo [18] as well as in cultured human promyelo-cytic leukemia HL-60 [19] and human myeloid ML-1acells [20].Resveratrol, a phytoalexin present in grapes and redwine, inhibited TPA-induced phosphorylation of I
j
B
a
andsubsequent p65 nuclear translocation in mouse skin byblocking IKK 
a
and IKK 
b
[21]. A previous study from ourlaboratory has revealed that resveratrol rescues PC12 cellsfrom oxidative stress via Nrf2-driven induction of hemeoxygenase-1 (HO-1) expression [22].The green tea polyphenol EGCG also inhibited activa-tion of NF-
j
B and AP-1 thereby suppressing the COX-2induction in mouse skin in vivo and/or cultured humanmammary epithelial (MCF10A) cells [23]. EGCG alsoupregulated antioxidant enzymes by activating the Nrf2-ARE signaling pathway [24,25]. Sulforaphane, an isothiocyanate present in cruciferousvegetables such as broccoli, has been extensively investi-gated with regards to its ability to induce phase 2detoxification enzymes [26]. It activates Nrf2, possibly bymodifying the sensor cysteines present in Keap1 [27,28].
Fig. 2
Signal transduction pathways responsible for Nrf2-AREactivation. Nrf2 activation is regulated by two distinct cellularsignaling pathways in a manner similar to that applied to NF-
j
Bactivation signaling schematically represented in Fig.1. Uponstimulation of cells, activation of protein kinases such as PI3K,PKC, JNK, p38MAPK and ERK induce Nrf2 phosphorylation, whichfacilitates the dissociation of Nrf2 from its repressor Keap1 andsubsequent translocation to nucleus and interaction with the coacti-vator CBP/p300. Alternatively, prooxidants or electrophiles maydirectly interact with cysteine residues present in Keap1, therebystimulating Nrf2 dissociation. Both events can facilitate the nucleartranslocation of Nrf2, which subsequently associates with small Maf,forming a heterodimer binds to antioxidant-response element (ARE)or electrophile-responsive element (EpRE) to stimulate phase IIdetoxification or antioxidant enzymes. Chemopreventive phytochemi-cals can activate Nrf2 signaling by inducing phosphorylation of Nrf2via activation of the upstream kinases and/or through oxidation/ modification of Keap1 cysteine thiolsGenes Nutr (2008) 2:313–317 315
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