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

Oncogene volume 23, pages 1845–1853 (2004)Cite this article

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.

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Abbreviations

MMP:

matrix metalloproteinase

NF-κB:

nuclear factor-κB

PMA:

phorbol myristate acetate

AP:

activator protein

RT–PCR:

reverse transcription–PCR

WT:

wild type

PKC:

protein kinase C

MAPK:

mitogen-activated protein kinase

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Acknowledgements

This work was supported by a Korea Research Foundation Grant (KRF-2001-041-F00009) and partially supported by the Korea Science and Engineering Foundation (KOSEF) through the MRC at Keimyung University (R13-2002-028-01002-0).

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Author notes

  1. Ju-Hyung Woo and Jun Hee Lim: Both these authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, South Korea

    Ju-Hyung Woo, Jun Hee Lim, Young-Ho Kim, Jong-Wook Park & Taeg Kyu Kwon

  2. Department of Microbiology, School of Medicine, Keimyung University, 194 DongSan-Dong, Taegu, 700-712, Korea

    Seong-Il Suh

  3. Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea

    Do Sik Min

  4. Department of Life Science, Daejin University, Pochon-gun, Kyeonggido, South Korea

    Jong-Soo Chang

  5. Department of Biochemistry, College of Medicine, Yeungnam University, Taegu, South Korea

    Young Han Lee

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Correspondence to Taeg Kyu Kwon.

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Woo, JH., Lim, J., Kim, YH. et al. Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC δ signal transduction. Oncogene 23, 1845–1853 (2004). https://doi.org/10.1038/sj.onc.1207307

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