Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-alpha.
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.
Hwang
Mun Kyung
MK
Department of Agricultural Biotechnology, Seoul National University, Republic of Korea.
Kang
Nam Joo
NJ
Heo
Yong-Seok
YS
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
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*
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