Polyphenon E Inhibits the Growth of Human Barrett's and Aerodigestive Adenocarcinoma Cells by Suppressing Cyclin D1 Expression

Abstract

Green tea consumption has been shown to exhibit cancer-preventive activities in preclinical studies. Polyphenon E (Poly E) is a well-defined green tea-derived catechin mixture. This study was designed to determine the effects of Poly E on the growth of human Barrett's and aerodigestive adenocarcinoma cells and the mechanisms involved in growth regulation by this agent. Human adenocarcinoma cells and immortalized Barrett's epithelial cells were used as model systems. Poly E inhibited the proliferation of immortalized Barrett's cells as well as various adenocarcinoma cells, and this was associated with the down-regulation of cyclin D1 protein expression. Inhibition of cyclin D1 led to dephosphorylation of the retinoblastoma protein in a dose-dependent manner; these changes were associated with G(1) cell cycle arrest. Poly E down-regulated cyclin D1 promoter activity and mRNA expression, suggesting transcriptional repression, and this correlated with decreased nuclear beta-catenin and beta-catenin/TCF4 transcriptional activity. MG132, an inhibitor of 26S proteosome, blocked the Poly E-induced down-regulation of cyclin D1, and Poly E promoted cyclin D1 polyubiquitination, suggesting that Poly E also inhibits cyclin D1 expression by promoting its degradation. Poly E inhibits growth of transformed aerodigestive epithelial cells by suppressing cyclin D1 expression through both transcriptional and posttranslational mechanisms. These results provide insight into the mechanisms by which Poly E inhibits growth of Barrett's and adenocarcinoma cells, and provides a rationale for using this agent as a potential chemopreventive and therapeutic strategy for esophageal adenocarcinoma and its precursor, Barrett's esophagus.