Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-alpha

Biochem Pharmacol. 2009 Apr 1;77(7):1213-22. doi: 10.1016/j.bcp.2008.12.021. Epub 2009 Jan 7.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthocyanins / administration & dosage*
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Drug Delivery Systems / methods
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • Mice
  • Plants
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins c-fyn / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-fyn / biosynthesis*
  • Tumor Necrosis Factor-alpha / administration & dosage*


  • Anthocyanins
  • Cyclooxygenase 2 Inhibitors
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-fyn
  • delphinidin