Epigallocatechin-3 gallate induces growth inhibition and apoptosis in human breast cancer cells through survivin suppression

Int J Oncol. 2007 Oct;31(4):705-11.

Abstract

Recent investigations have demonstrated that polyphenolic catechins inhibit cancer cell proliferation and tumor growth. However, how the major active component of tea catechins, epigallocatechin-3 gallate (EGCG), mediates anticancerous effects has not been extensively examined. We have investigated the cell growth inhibitory effects of EGCG on cell growth of the human breast cancer cell line MCF-7, and the mechanism of its action with emphasis on the regulation of tumor cell survival. A significant EGCG dose-dependent growth inhibition was observed coordinated with EGCG-induced apoptosis. Analysis of survivin expression after addition of EGCG showed that both survivin mRNA and protein were decreased. The survivin-promoter luciferase activity in EGCG-treated cells was significantly inhibited by 91+/-2.0% (P<0.001), compared with the control. Interestingly, EGCG strongly inhibited the basal activation of phospho-AKT and AKT kinase activity as early as 30 min after treatment. Furthermore, inhibition of AKT kinase activity by EGCG preceded the suppression of survivin (1 h post treatment), followed by increased caspase-9 activity (6 h post treatment). A dominant negative AKT or the phosphatidylinositol 3-kinase inhibitor, LY294002, also strongly inhibited survivin promoter activity, providing further evidence to support the hypothesis that the inhibitory effect of EGCG on survivin is mediated via the AKT pathway. Therefore, EGCG is a potent proapoptotic agent in MCF-7 breast cancer cells that targets survivin expression via suppression of the AKT pathway.

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Line, Tumor
  • Colony-Forming Units Assay
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Luciferases / metabolism
  • Microtubule-Associated Proteins / antagonists & inhibitors*
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • Protease Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Survivin

Substances

  • Anticarcinogenic Agents
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Protease Inhibitors
  • Survivin
  • Catechin
  • epigallocatechin gallate
  • Luciferases
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt