TitleDelphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blocking Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling.
Publication TypeJournal Article
Year of Publication2008
AuthorsKang, NJoo, Lee, KWon, Kwon, JYeon, Hwang, MKyung, Rogozin, EA, Heo, Y-S, Bode, AM, Lee, HJoo, Dong, Z
JournalCancer Prev Res (Phila)
Volume1
Issue7
Pagination522-31
Date Published2008 Dec
ISSN1940-6215
KeywordsAnimals, Anthocyanins, Blotting, Western, Cell Line, Cell Transformation, Neoplastic, Cyclooxygenase 2, Epithelial Cells, Extracellular Signal-Regulated MAP Kinases, Gene Expression, Mice, Mitogen-Activated Protein Kinase Kinases, raf Kinases, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
Abstract

Recent studies suggest that anthocyanidins play a pivotal role in the chemopreventive effects of fruits and vegetables. However, the underlying molecular mechanisms and cellular targets remain unknown. Neoplastic transformation of cells and inflammation are considered to be major events contributing to carcinogenesis. Here, we report that delphinidin, a major dietary anthocyanidin, inhibits tumor promoter-induced transformation and cyclooxygenase-2 (COX-2) expression in JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells by directly targeting Raf and mitogen-activated protein kinase kinase (MEK). Delphinidin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation and COX-2 expression at both the protein and transcriptional levels. The activation of activator protein-1 and nuclear factor-kappaB induced by TPA was dose dependently inhibited by delphinidin treatment. Delphinidin strongly suppressed Raf1 and MEK1 kinase activities and subsequently attenuated TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase (ERK), p90RSK, and MSK. Although delphinidin suppressed ERK and c-Jun NH(2)-terminal kinase activities, it was more effective at inhibiting Raf1 or MEK1 activities. Pull-down and competition assays revealed that delphinidin binds with Raf1 or MEK1 noncompetitively with ATP. Delphinidin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor and H-Ras, both of which are involved in the activation of Raf/MEK/ERK signaling. Together, these findings suggested that the targeted inhibition of Raf1 and MEK activities and COX-2 expression by delphinidin contribute to the chemopreventive potential of fruits and vegetables.

DOI10.1158/1940-6207.CAPR-08-0071
Alternate JournalCancer Prev Res (Phila)
PubMed ID19139002
PubMed Central IDPMC2832759
Grant ListP01 CA027502-270022 / CA / NCI NIH HHS / United States
R01 CA077646 / CA / NCI NIH HHS / United States
CA 120388 / CA / NCI NIH HHS / United States
CA 081064 / CA / NCI NIH HHS / United States
CA 077646 / CA / NCI NIH HHS / United States
R37 CA081064 / CA / NCI NIH HHS / United States
R01 CA111536 / CA / NCI NIH HHS / United States
CA 111536 / CA / NCI NIH HHS / United States
R01 CA111536-05 / CA / NCI NIH HHS / United States
R01 CA081064-08 / CA / NCI NIH HHS / United States
R01 CA120388 / CA / NCI NIH HHS / United States
CA 027502 / CA / NCI NIH HHS / United States
R01 CA120388-04 / CA / NCI NIH HHS / United States
R01 CA077646-10 / CA / NCI NIH HHS / United States
P01 CA027502 / CA / NCI NIH HHS / United States
R01 CA081064 / CA / NCI NIH HHS / United States