title: Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals.
abstract: The incidence of skin cancer is increasing worldwide. Over the last several decades, attention has been focused on understanding the molecular basis of skin carcinogenesis and identifying substances for use in chemoprevention of skin cancer. Reactive oxygen species generated by chemical carcinogens or UV irradiation play a key role in skin tumorigenesis. Multiple lines of evidence suggest that cellular antioxidant and/or phase-2 detoxification enzymes, collectively known as cytoprotective proteins, can protect against skin carcinogenesis. A redox sensitive transcription factor, nuclear factor-erythroid related factor-2 (Nrf2), is a master regulator of transcriptional activation of genes encoding cytoprotective proteins. Many chemopreventive phytochemicals are known to activate Nrf2 either by oxidative or covalent modification of its cytosolic repressor Kelch-like ECH-associated protein (Keap1) or by phosphorylation of Nrf2. Upon activation, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoter regions of genes encoding cytoprotective proteins. Mice genetically deficient in Nrf2 are highly susceptible to chemically induced skin tumorigenesis and are less responsive to the cytoprotective effects of some chemopreventive phytochemicals. This article highlights the Nrf2-ARE signaling as a prime target for chemoprevention of skin cancer with some phytochemicals.
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Chun
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Juthika
authors.initials: J
authors.lastname: Kundu
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea; Cancer Research Institute Seoul National University, Seoul 110-744, South Korea. Electronic address: surh@snu.ac.kr.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001711:Biotransformation; D063646:Carcinogenesis / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000187:drug effects*; D064209:Phytochemicals / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*
chemical_list: D016588:Anticarcinogenic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D064209:Phytochemicals
keywords: Antioxidant response elements; Chemoprevention; Heme oxygenase-1; Nrf2; Phytochemicals; Skin cancer