title: Green tea polyphenol EGCG suppresses Wnt/β-catenin signaling by promoting GSK-3β- and PP2A-independent β-catenin phosphorylation/degradation.
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.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, Republic of Korea.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
authors.forename: Jungsug
authors.initials: J
authors.lastname: Gwak
authors.forename: Seoyoung
authors.initials: S
authors.lastname: Park
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D059808:Polyphenols / Q000302:isolation & purification / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction; D013662:Tea / Q000737:chemistry; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D016588:Anticarcinogenic Agents; C495270:CTNNB1 protein, human; D059808:Polyphenols; D047428:Protein Kinase Inhibitors; D013662:Tea; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; D002392:Catechin; C045651:epigallocatechin gallate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex
keywords: (−)-epigallocatechin-3-gallate; Wnt/β-catenin signaling; colon cancer; phosphorylation; proteasomal degradation