Ju-Hyung Woo^1,6, Jun Hee Lim^1,6, Young-Ho Kim¹, Seong-Il Suh², Do Sik Min³, Jong-Soo Chang⁴, Young Han Lee⁵, Jong-Wook Park¹ and Taeg Kyu Kwon^1,*

¹Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, South Korea
²Department of Microbiology, School of Medicine, Keimyung University, 194 DongSan-Dong, Taegu 700-712, Korea
³Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea
⁴Department of Life Science, Daejin University, Pochon-gun, Kyeonggido, South Korea
⁵Department of Biochemistry, College of Medicine, Yeungnam University, Taegu, South Korea

^*Correspondence: TK Kwon

⁶Both these authors contributed equally to this work

Received 11 July 2003; Revised 20 October 2003; Accepted 21 October 2003; Published online 8 December 2003.

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-κB response element. Resveratrol inhibited PMA-mediated activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)-δ activation. Therefore, we conclude that the MMP-9 inhibition activity of resveratrol and its inhibition of JNK and PKC-δ may have a therapeutic potential, given that a novel means of controlling growth and invasiveness of tumors.

Keywords: resveratrol, matrix metalloproteinase-9, NF-κB, PMA, PKC, JNK

Abbreviations: MMP, matrix metalloproteinase; NF-B, nuclear factor-B; PMA, phorbol myristate acetate; AP, activator protein; RT-PCR, reverse transcription-PCR; WT, wild type; PKC, protein kinase C; MAPK, mitogen-activated protein kinase