Association of suppression of extracellular signal-regulated kinase phosphorylation by epigallocatechin gallate with the reduction of matrix metalloproteinase activities in human fibrosarcoma HT1080 cells.
J Agric Food Chem 2003 Mar 26;51(7):1858-63
Maeda-Yamamoto M; Suzuki N; Sawai Y; Miyase T ; Sano M; Hashimoto-Ohta A; Isemura M
National Institute of Vegetable and Tea Science, NARO, 2769 Kanaya, Shizuoka 428-8501, Japan. firstname.lastname@example.org .
Matrix metalloproteinases (MMPs) play a crucial role in the process of cancer invasion and metastasis. Previous findings suggested that epigallocatechin gallate (EGCG), a main flavanol of green tea, caused decreased levels of MMP-2 and MMP-9 activities to be secreted into culture medium. To obtain further information on EGCG-mediated regulation of these MMPs, the effects of EGCG on enzyme activity, mRNA expression, and mitogen-activated protein kinase (MAPK) activities in human fibrosarcoma HT1080 cells were examined. EGCG was confirmed to suppress the gelatin-degrading activities due to MMP-2 and MMP-9 in the culture medium. This suppression of enzyme activities by EGCG was consistent with the decreased levels of MMP-2 and MMP-9 mRNAs. EGCG-mediated suppression was also observed for MT1-MMP mRNA. EGCG-mediated suppression of the level of MMP-9 transcript was correlated with its suppression of MMP-9 promoter activity. EGCG inhibited the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are the members of an MAPK family necessary for MMP-9 up-regulation. EGCG also suppressed p38 MAPK activity but gave no effects on stress-activated protein kinase/c-Jun N-terminal kinase activity. These findings suggest that suppression of ERK phosphorylation by EGCG is involved in the inhibition of expression for MMP-2 and MMP-9 mRNAs, leading to the reduction of their enzyme activities of the cancer cells. Methyl derivatives, epigallocatechin-3-O-(3-O-methyl) gallate and epigallocatechin-3-O-(4-O-methyl) gallate, exhibited effects similar to, but weaker than, those of EGCG, suggesting the important role of an unsubstituted triphenolic ester structure in these activities.