Regulation of NF-E2-Related Factor 2 Signaling for Cancer Chemoprevention: Antioxidant Coupled with Antiinflammatory

^{Department of Physiology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.}

^{Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey.}

^{Department of Neurosurgery, The Vivian L. Smith Center for Neurologic Research, The University of Texas-Health Science Center at Houston, Houston, Texas.}

^{Corresponding author.}

Prof. Rong Hu, Department of Physiology, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. E-mail:Email: moc.liamtoh@uhlehcim

Dr. Rong Yu, Department of Neurosurgery, The Vivian L. Smith Center for Neurologic Research, The University of Texas-Health Science Center at Houston, 6431 Fannin St., Room 7.134. Houston, TX 77030. E-mail:Email: ude.cmt.htu@uy.gnor

Address correspondence to: Prof. Ah-Ng Tony Kong, Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail:ude.sregtur.ycamrahp@tgnokProf. Rong Hu, Department of Physiology, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. E-mail:Email: moc.liamtoh@uhlehcimDr. Rong Yu, Department of Neurosurgery, The Vivian L. Smith Center for Neurologic Research, The University of Texas-Health Science Center at Houston, 6431 Fannin St., Room 7.134. Houston, TX 77030. E-mail:Email: ude.cmt.htu@uy.gnor

Received 2010 Apr 30; Revised 2010 May 8; Accepted 2010 May 9.

Abstract

Cancer chemoprevention is a process of using either natural or synthetic compounds to reduce the risk of developing cancer. Observations that NF-E2-related factor 2 (Nrf2)-deficient mice lack response to some chemopreventive agents point to the important role of Nrf2 in chemoprevention. Nrf2 is a member of basic-leucine zipper transcription factor family and has been shown to regulate gene expression by binding to a response element, antioxidant responsive element. It is generally believed that activation of Nrf2 signaling is an adaptive response to the environmental and endogenous stresses. Under homeostatic conditions, Nrf2 is suppressed by association with Kelch-like ECH-associated protein 1 (Keap1), but is stimulated upon exposure to oxidative or electrophilic stress. Once activated, Nrf2 translocates into nuclei and upregulates a group of genes that act in concert to combat oxidative stress. Nrf2 is also shown to have protective function against inflammation, a pathological process that could contribute to carcinogenesis. In this review, we will discuss the current progress in the study of Nrf2 signaling, in particular, the mechanisms of Nrf2 activation by chemopreventive agents. We will also discuss some of the potential caveats of Nrf2 in cancer treatment and future opportunity and challenges on regulation of Nrf2-mediated antioxidant and antiinflammatory signaling in the context of cancer prevention. Antioxid. Redox Signal. 13, 1679–1698.

Abstract

Abbreviations Used

ACF	aberrant crypt foci
AOM	azoxymethane
ARE	antioxidant responsive element
BaP	benzo[a]pyrene
BBN	N-nitrosobutyl(4-hydroxybutyl)amine
bNLS	bipartite nuclear localization signal at the basic region
BTB	broad complex, tramtrack, and bric a brac
bZip	basic-leucine zipper
CNC	Cap ’n’ Collar
CRC	colorectal cancer
CTR	C-terminal region
D3T	3H-1,2-dithiole-3-thione
DGR	double glycine/Kelch repeat region
DLG	(formulated as) L-X-X-Q-D-X-D-L-G
DMBA	7,12-dimethylbenz(a)anthracene
DSS	dextran sulfate sodium
EGFP	green fluorescence protein
ERK2	extracellular signal-regulated protein kinase 2
ETGE	(formulated as) D/N-X-E-T/-S-G-E
fNrf2	free-floating Nrf2
gpt	guanine phosphoribosyltransferase
GST	glutathione S-transferase
HO-1	heme oxygenase-1
IQ	2-amino-3-methylimidazo[4,5-f]quinoline
IVR	intervening region
JNK1	c-Jun NH(2)-terminal kinase-1
Keap1	Kelch-like ECH-associated protein 1
kNrf2	Keap1-binding Nrf2
Maf	musculoaponeurotic fibrosarcoma
MAPKs	mitogen-activated protein kinases
Neh	Nrf2-ECH homology
NES	nuclear exporting signal
NES_TA	nuclear exporting signal at transactivation (TA) domain
NESzip	nuclear exporting signal in the ZIP dimerization domain
NF-κB	nuclear factor-kappa-B
NLS	nuclear localization signal
NLS_C	monopartite NLS at the carboxyl-terminus
NLS_N	monopartite NLS at the amino-terminus
NQO1	NAD(P)H:quinone oxidoreductase 1
Nrf2	NF-E2-related factor 2
Nrf2 KO	Nrf2 knockout
Nrf2 WT	wild-type mice with intact Nrf2 function
NTR	N-terminal region
PCa	prostate cancer
PERK	PKR-like endoplasmic reticulum kinase
PI3K	phosphatidylinositol 3-kinase
PIN	prostatic intraepithelial neoplasia
PKC	protein kinase C
Rb	retinoblastoma
RNS	reactive nitrogen species
ROS	reactive oxygen species
SFN	sulforaphane
SV40	simian virus 40
tBHQ	tert-butylhydroquinone
TPA	12-O-tetradecanoylphorbol-13-acetate
TRAMP	transgenic adenocarcinoma mouse prostate
Ub	ubiquitination
UGT	UDP-glucuronosyltransferase

Abbreviations Used

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