Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by apigenin via the inhibition of p38 mitogen-activated protein kinase-dependent matrix metalloproteinase-9 expression.
Apigenin has special interest for the development of chemopreventive agents against cancer because it is a widely distributed plant flavonoid that has antitumor properties. In this study, we investigated the apigenin effects on the protease-mediated invasiveness in human metastatic cancer cell lines Caski, SK-Hep1, and MDA-231. We found that apigenin markedly inhibits the phorbol-12-myristate-13-acetate (PMA)-induced increase in MMP-9 expression and activity in several cancer cell lines. These effects of apigenin are dose-dependent and correlate with the suppression of MMP-9 mRNA expression levels. PMA caused about a 5-fold induction in MMP-9 promoter activity, which was also suppressed by apigenin treatment in Caski cells. We found that apigenin could inhibit PMA-induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which was involved in the down-regulation of the expression of matrix metalloproteinase-9 (MMP-9) at mRNA levels. Furthermore, the treatment of inhibitors specific for p38 MAPK (SB203580) to Caski cells caused the reduction of MMP-9 expression. Restoration of p38 expression partly increased PMA-induced MMP-9 secretion blocked by apigenin treatment in Caski cells. These results showed apigenin might inhibit the invasion and migration abilities of Caski cells by reducing the MMP-9 expression through suppressing the p38 MAPK signaling pathway. These findings indicate that apigenin might be a useful strategy for controlling metastasis and the invasiveness of tumors.
Noh
Hyo-Jeong
HJ
Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
Sung
Eon-Gi
EG
Kim
Joo-Young
JY
Lee
Tae-Jin
TJ
Song
In-Hwan
IH
D047310:Apigenin / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D047310:Apigenin; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate