title: Cyanidin suppresses ultraviolet B-induced COX-2 expression in epidermal cells by targeting MKK4, MEK1, and Raf-1.
abstract: Skin cancer is the most frequently diagnosed cancer in the United States. Ultraviolet B (UVB) rays (wavelength: 280-320nm) play a pivotal role in the development of skin cancer by inducing the expression of inflammatory proteins such as cyclooxygenase-2 (COX-2). Cyanidin, the most plentiful of the plant pigments known as anthocyanidins, is a potent chemopreventive agent. In the present study, we examined the molecular mechanisms underlying the chemopreventive activity of cyanidin and identified its molecular targets. Cyanidin inhibited UVB-induced COX-2 expression and prostaglandin E(2) secretion in the epidermal skin cell line JB6 P+ by suppressing the transactivation of nuclear factor-kappaB and activator protein-1 which are well-known transcription factors regulated by mitogen-activated protein kinase. Cyanidin markedly inhibited the phosphorylation of JNK1/2, ERK1/2, and MEK1/2 than the of MKK4 and Raf-1, two upstream kinases of JNK1/2, ERK1/2, and MEK1/2. Cyanidin significantly suppressed the activities of MKK4, MEK1, and Raf-1 through direct binding. Transient transfection of a small interfering RNA specific for MKK4 inhibited the UVB-induced expression of COX-2 in JB6 P+ cells, as did the expression of a dominant-negative ERK2 mutant. We conclude that MKK4, MEK1, and Raf-1 are targets of cyanidin for the suppression of UVB-induced COX-2 expression.
authors.affiliation: WCU, Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Republic of Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Kwon
authors.forename: Sang Kwon
authors.initials: SK
authors.lastname: Seo
authors.forename: Joe Eun
authors.initials: JE
authors.lastname: Son
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: So Yun
authors.initials: SY
authors.lastname: Min
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects*; D015232:Dinoprostone / Q000096:biosynthesis; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D047468:Immunoprecipitation; D048369:MAP Kinase Kinase 1 / Q000187:drug effects* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000872:Anthocyanins; D018808:Transcription Factor AP-1; C017154:cyanidin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482127:Map2k1 protein, mouse; D015232:Dinoprostone