Dykellic Acid Inhibits Phorbol Myristate Acetate-induced Matrix Metalloproteinase-9 Expression by Inhibiting Nuclear Factor κB Transcriptional Activity

Abstract

Proteolytic degradation of the extracellular matrix and tumor metastasis correlate with expression of endopeptidases known as matrix metalloproteinases (MMPs). Expression of MMPs is regulated by cytokines and signal transduction pathways, including those activated by phorbol myristate acetate. We found that dykellic acid, a fungal metabolite, significantly inhibits the phorbol myristate acetate-induced increase in MMP-9 expression and activity. These effects of dykellic acid are time- and dose-dependent, and correlate with decreased MMP-9 promoter activity and mRNA expression. Whereas this compound does not affect DNA binding activity of nuclear factor κB (NFκB), dykellic acid does inhibit transactivation of NFκB. These data demonstrate a role for NFκB in the regulation of MMP-9 expression and the ability of dykellic acid to suppress this action of NFκB.