Inhibition of β-catenin signaling in human colon cancer cells and Apc^Min mice by (-)-Epigallocatechin-3-gallate

4889

Previously, we reported that oral administration of (-)-epigallocatechin-3-gallate (EGCG), a major catechin in green tea, not only inhibited small intestinal tumor formation in Apc^Min mice but also resulted in decreases of nuclear β-catenin and c-Myc levels and increases of E-cadherin levels in small intestinal tumors (Cancer Res, 2005; 65(22): in press). The purpose of present study was to investigate mechanisms involved in the inhibition of aberrant β-catenin signaling by EGCG in vitro and in vivo. In HCT116 human colon cancer cells, treatment with EGCG at concentrations of 20, 50, and 100 μM decreased the levels of nuclear β-catenin but increased the levels of E-cadherin, which is a similar finding to our previous results in another human colon cancer cell line, HT29 (Cancer Res, 2005; 65(22): in press). The EGCG treatment also suppressed important upstream events for the release of β-catenin from plasma membrane to cytoplasm and the degradation of E-cadherin; levels of tyrosine phosphorylation of β-catenin and p120^ctn as well as the phosphorylation (Thr 12) of Fyn were decreased under the EGCG treatment. In studies with 14-week old Apc^Min/+ mice, small intestinal tumors were found to have higher levels of IGF-1R and Fyn than normal small intestine tissues. In both normal and tumor tissues from Apc^Min/+ mice that were given intragastric administration of EGCG (75 mg/kg) 3 h before sacrifice, phosphorylation levels of IGF-1R, Fyn, β-catenin, and p120^ctn were decreased as compared to the levels in the normal and tumor tissues from control mice. These results suggest that EGCG suppresses abberant β-catenin signaling possibly through inhibition of phosphorylation of β-catenin, p120^ctn, IGF-1R, and Fyn, and these effects may contribute to the inhibition of tumorigenesis in Apc^Min mice (supported by NIH grant CA 88961).