Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction.
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-kappaB response element. Resveratrol inhibited PMA-mediated activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)-delta activation. Therefore, we conclude that the MMP-9 inhibition activity of resveratrol and its inhibition of JNK and PKC-delta may have a therapeutic potential, given that a novel means of controlling growth and invasiveness of tumors.
Woo
Ju-Hyung
JH
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, South Korea.
Lim
Jun Hee
JH
Kim
Young-Ho
YH
Suh
Seong-Il
SI
Min
Do Sik
DS
Chang
Jong-Soo
JS
Lee
Young Han
YH
Park
Jong-Wook
JW
Kwon
Taeg Kyu
TK
D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001483:Base Sequence; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017931:DNA Primers; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051745:Protein Kinase C-delta; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D002583:Uterine Cervical Neoplasms
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D016328:NF-kappa B; D013267:Stilbenes; D018808:Transcription Factor AP-1; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol