(-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells

Carcinogenesis. 2005 Sep;26(9):1553-62. doi: 10.1093/carcin/bgi104. Epub 2005 Apr 28.

Abstract

Matrix metalloproteinase (MMP)-7 (matrilysin-1) plays significant roles in the growth, invasion, and metastasis of colorectal tumors, while (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol with chemopreventive properties, has been shown to be an inhibitor of MMP-2 and MMP-9. In the present study, HT-29 human colorectal cancer cells were treated with EGCG to examine its effects on pro-MMP-7 induction and production using RT-PCR and western blot analyses. Surprisingly, EGCG (10-100 microM) treatment increased both intracellular and extracellular pro-MMP-7 protein levels (2.6-8.4-fold and 1.9-6.4-fold, respectively) in dose- and time-dependent manner, with a significant upregulation of its mRNA expression. EGCG also activated extracellular signal-regulated protein kinase (ERK)1/2, c-JUN NH2-terminal kinase (JNK)1/2 and p38 mitogen-activated protein kinase (MAPK), as previously reported. In addition, the polyphenol triggered the phosphorylation of c-JUN (Ser63 and Ser73) and induced c-JUN/c-FOS, thereby increasing the DNA binding activity of activator protein-1 (AP-1), as shown by an AP-1 luciferase reporter assay. Pharmacological blockade of MAPK activities suggested that pro-MMP-7 expression was induced via JNK1/2 activation, but not in the case of ERK1/2 or p38 MAPK. N-Acetyl-L-cysteine, superoxide (O2-) dismutase and catalase attenuated the EGCG-induced pro-MMP-7 production, suggesting an involvement of oxidative stress in these events. Conversely, EGCG spontaneously generated O2- in a cell-free system that utilized a cytochrome C reduction method. Further, (-)-epicatechin-3-gallate (25 and 100 microM) and green tea polyphenols (33 and 132 microg/ml) induced pro-MMP-7 expression, whereas (-)-epicatechin and (-)-epigallocatechin (100 microM each) did not. Induction of pro-MMP-7 expression by EGCG was also shown in another human colorectal adenocarcinoma cell line, Caco-2. Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Line, Tumor
  • Colorectal Neoplasms
  • Enzyme Activation
  • Enzyme Precursors / genetics*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Matrix Metalloproteinase 7 / genetics*
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Mitogen-Activated Protein Kinase 9 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anticarcinogenic Agents
  • Enzyme Precursors
  • Catechin
  • epigallocatechin gallate
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 8
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 7