title: Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-alpha.
abstract: Tumor necrosis factor (TNF)-alpha-mediated cyclooxygenase (COX)-2 expression plays key roles in inflammation and tumorigenesis, particularly skin carcinogenesis, and hence targeting the TNF-alpha-mediated signaling pathway might be a promising strategy for developing chemopreventive agents against skin cancer and other skin disorders. Here we report that Fyn kinase - one of the members of the nonreceptor protein tyrosine kinase family - is involved in TNF-alpha-induced COX-2 expression, and that delphinidin - a major anthocyanidin present in red wine and berries - inhibits these effects by directly inhibiting Fyn kinase activity. Delphinidin strongly inhibited TNF-alpha-induced COX-2 expression in JB6 P+ mouse epidermal (JB6 P+) cells, whereas two other major phenolic compounds (resveratrol and gallic acid) did not exert significant inhibitory effects. Delphinidin inhibited the TNF-alpha-induced phosphorylations of JNK, p38 MAP kinase, Akt, p90RSK, MSK1, and ERK, and subsequently blocked the activation of the eukaryotic transcription factors AP-1 and NF-kappaB. Kinase and pull-down assay data revealed that delphinidin inhibited Fyn kinase activity and directly bound with Fyn kinase noncompetitively with ATP. By using PP2 (a commercial inhibitor of Fyn kinase) and siRNA-Fyn, we confirmed that Fyn kinase is involved in TNF-alpha-induced COX-2 expression mainly by down-regulating JNK in JB6 P+ cells. Together these findings suggest that the targeted inhibition of Fyn kinase activity and COX-2 expression by delphinidin contributes to the chemopreventive potential of red wine and berries.
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Republic of Korea.
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
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 / Q000008:administration & dosage*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010944:Plants; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D000872:Anthocyanins; D052246:Cyclooxygenase 2 Inhibitors; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D051076:Proto-Oncogene Proteins c-fyn; C017185:delphinidin