Nrf2 as a novel molecular target for chemoprevention.
One of the rational and effective strategies for chemoprevention is the blockade of DNA damage caused by carcinogenic insult. This can be achieved either by reducing the formation of reactive carcinogenic species or stimulating their detoxification. A wide spectrum of xenobiotic metabolizing enzymes catalyze both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions involved in carcinogen activation and/or deactivation. Several antioxidant-response element (ARE)-regulated gene products such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, UDP-glucuronosyltransferase, gamma-glutamate cysteine ligase, and hemeoxygenase-1 are known to mediate detoxification and/or to exert antioxidant functions thereby protecting cells from genotoxic damage. The transcription of ARE-driven genes is regulated, at least in part, by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2), which is sequestered in cytoplasm by Kelch-like ECH-associated protein 1 (Keap1). Exposure of cells to ARE inducers results in the dissociation of Nrf2 from Keap1 and facilitates translocation of Nrf2 to the nucleus, where it heterodimerizes with small Maf protein, and binds to ARE, eventually resulting in the transcriptional regulation of target genes. The Nrf2-Keap1-ARE signaling pathway can be modulated by several upstream kinases including phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases. Selected Nrf2-Keap1-ARE activators, such as oltipraz, anethole dithiolethione, sulforaphane, 6-methylsulphinylhexyl isothiocyanate, curcumin, caffeic acid phenethyl ester, 4'-bromoflavone, etc. are potential chemopreventive agents. This mini-review will focus on a chemopreventive strategy directed towards protection of DNA and other important cellular molecules by inducing de novo synthesis of phase II detoxifying or antioxidant genes via the Nrf2-ARE core signaling pathway.
Lee
Jeong-Sang
JS
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
Surh
Young-Joon
YJ
D000975:Antioxidants / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D018890:Chemoprevention; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D016350:Leucine Zippers; D051267:NF-E2-Related Factor 2; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D000975:Antioxidants; D002273:Carcinogens; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015534:Trans-Activators; D011494:Protein Kinases