Green tea polyphenol, (-)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting β-catenin signaling

The green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), has been shown to have anti-carcinogenic effects in several skin tumor models, and efforts are continued to investigate the molecular targets responsible for its cytotoxic effects to cancer cells. Our recent observation that beta-catenin is upregulated in skin tumors suggested the possibility that the anti-skin carcinogenic effects of EGCG are mediated, at least in part, through its effects on beta-catenin signaling. We have found that treatment of the A431 and SCC13 human skin cancer cell lines with EGCG resulted in reduced cell viability and increased cell death and that these cytotoxic effects were associated with inactivation of beta-catenin signaling. Evidence of EGCG-induced inactivation of beta-catenin included: (i) reduced accumulation of nuclear beta-catenin; (ii) enhanced levels of casein kinase1 alpha, reduced phosphorylation of glycogen synthase kinase-3 beta, and increased phosphorylation of beta-catenin on critical Serille(45,33137) residues; and (iii) reduced levels of matrix metalloproteinase (MMP)-2 and MMP-9, which are down-stream targets of beta-catenin. Treatment of cells with prostaglandin E2 (PGE(2)) enhanced the accumulation of beta-catenin and enhanced beta-catenin signaling. Treatment with either EGCG or an EP2 antagonist (AH6809) reduced the PGE(2)-enhanced levels of cAMP, an upstream regulator of beta-catenin. Inactivation of beta-catenin by EGCG resulted in suppression of cell-survival signaling proteins. siRNA knockdown of beta-catenin in A431 and SCC13 cells reduced cell viability. Collectively, these data suggest that induction of cytotoxicity in skin cancer cells by EGCG is mediated by targeting of beta-catenin signaling and that the beta-catenin signaling is upregulated by inflammatory mediators. (C) 2013 Elsevier Inc. All rights reserved.