Green tea polyphenol EGCG suppresses Wnt/β‐catenin signaling by promoting GSK‐3β‐ and PP2A‐independent β‐catenin phosphorylation/degradation. (29th October 2014) - Oh, Sangtaek
Abstract (−)‐Epigallocatechin‐3‐gallate (EGCG), the major polyphenol in green tea, has been reported to inhibit the Wnt/β‐catenin pathway, which is aberrantly up‐regulated in colorectal cancers, but its precise mechanism of action remains unclear. Here, we used a sensitive cell‐based system to demonstrate that EGCG suppresses β‐catenin response transcription (CRT), activated by Wnt3a‐conditioned medium (Wnt3a‐CM), by promoting the degradation of intracellular β‐catenin. EGCG induced β‐catenin N‐terminal phosphorylation at the Ser33/37 residues and subsequently promoted its degradation; however, this effect was not observed for oncogenic forms of β‐catenin. Pharmacological inhibition or depletion of glycogen synthase kinase‐3β (GSK‐3β) did not abrogate the EGCG‐mediated β‐catenin degradation. EGCG did not affect the activity and expression of protein phosphatase 2A (PP2A). Consistently, the phosphorylation and degradation of β‐catenin was found in adenomatous polyposis coli (APC) mutated colon cancer cells after EGCG treatment. EGCG repressed the expression of cyclin D1 and c‐myc, which are β‐catenin/T‐cell factor‐dependent genes, and inhibited the proliferation of colon cancer cells. Our findings suggest that EGCG exerts its cancer‐preventive or anticancer activity against colon cancer cells by promoting the phosphorylation and proteasomal degradation of β‐catenin through a mechanism independent of the GSK‐3β and PP2A. © 2014 BioFactors, 40(6):586–595, 2014