Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction

Abstract

Proteolytic degradation of the extracellular matrix and tumor metastasis correlate with the expression of endopeptidases known as matrix metalloproteinases (MMPs). The expression of MMPs is regulated by cytokines and signal transduction pathways, including those activated by phorbol myristate acetate (PMA). We found that resveratrol, a phytoalexin present in grapes, significantly inhibits the PMA-induced increase in MMP- 9 expression and activity. These effects of resveratrol are dose dependent and correlate with the suppression of MMP-9 mRNA expression levels. PMA caused about a 23-fold increase in MMP-9 promoter activity, which was suppressed by resveratrol. Transient transfection utilizing MMP-9 constructs, in which specific transcriptional factors were mutagenized, indicated that the effects of PMA and resveratrol were mediated via an activator protein-1 and nuclear factor-jB response element. Resveratrol inhibited PMA-mediated activation of c-Jun Nterminal kinase (JNK) and protein kinase C (PKC)-d activation. Therefore, we conclude that the MMP-9 inhibition activity of resveratrol and its inhibition of JNK and PKC-d may have a therapeutic potential, given that a novel means of controlling growth and invasiveness of tumors. Oncogene (2004) 23, 1845–1853 doi:10.1038/sj.onc.1207307 Published online 8 December 2003 Keywords: resveratrol; matrix metalloproteinase-9; NF-kB; PMA; PKC; JNK