Delphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blockingraf/mitog en-activated protein kinase kinase/extracellular signal-regulated kinase signaling

Nam Joo Kang, Ki Won Lee, Jung Yeon Kwon, Mun Kyung Hwang, Evgeny A. Rogozin, Yong Seok Heo, Ann M. Bode, Hyong Joo Lee, Zigang Dong

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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-κB 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 NH2-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.

Original languageEnglish (US)
Pages (from-to)522-531
Number of pages10
JournalCancer Prevention Research
Volume1
Issue number7
DOIs
StatePublished - Dec 2008

Fingerprint

Dive into the research topics of 'Delphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blockingraf/mitog en-activated protein kinase kinase/extracellular signal-regulated kinase signaling'. Together they form a unique fingerprint.

Cite this