Activation of Antioxidant-Response Element (ARE), Mitogen-Activated Protein Kinases (MAPKs) and Caspases by Major Green Tea Polyphenol Components during Cell Survival and Death

Chi Chen, Rong Yu, Edward D. Owuor, A. N. Tony Kong

Research output: Contribution to journalArticlepeer-review

380 Scopus citations

Abstract

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in humar. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicrty in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 μM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MARK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 μM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTR.

Original languageEnglish (US)
Pages (from-to)605-612
Number of pages8
JournalArchives of Pharmacal Research
Volume23
Issue number6
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Apoptosis
  • Are-luciferase
  • Caspase-3
  • Catechin
  • EC
  • ECG
  • EGC
  • EGCG
  • ERK
  • Green tea polyphenols
  • Hela
  • Hepg2-are-c8
  • JNK
  • Map kinases
  • P38

Fingerprint

Dive into the research topics of 'Activation of Antioxidant-Response Element (ARE), Mitogen-Activated Protein Kinases (MAPKs) and Caspases by Major Green Tea Polyphenol Components during Cell Survival and Death'. Together they form a unique fingerprint.

Cite this