Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Toxicol Appl Pharmacol. 2013 Dec 1;273(2):418-24. doi: 10.1016/j.taap.2013.09.021. Epub 2013 Oct 3.
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 β-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 β-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 β-catenin signaling. Evidence of EGCG-induced inactivation of β-catenin included: (i) reduced accumulation of nuclear β-catenin; (ii) enhanced levels of casein kinase1α, reduced phosphorylation of glycogen synthase kinase-3β, and increased phosphorylation of β-catenin on critical serine(45,33/37) residues; and (iii) reduced levels of matrix metalloproteinase (MMP)-2 and MMP-9, which are down-stream targets of β-catenin. Treatment of cells with prostaglandin E2 (PGE2) enhanced the accumulation of β-catenin and enhanced β-catenin signaling. Treatment with either EGCG or an EP2 antagonist (AH6809) reduced the PGE2-enhanced levels of cAMP, an upstream regulator of β-catenin. Inactivation of β-catenin by EGCG resulted in suppression of cell survival signaling proteins. siRNA knockdown of β-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 β-catenin signaling and that the β-catenin signaling is upregulated by inflammatory mediators.
绿茶多酚（(-)-表没食子儿茶素没食子酸酯，EGCG）已被证明在几种皮肤肿瘤模型中具有抗癌作用，人们继续努力研究其对癌细胞产生细胞毒性作用的分子靶标。我们最近的观察表明，β-连环蛋白在皮肤肿瘤中上调，这表明 EGCG 的抗皮肤致癌作用至少部分是通过其对β-连环蛋白信号的作用来介导的。我们发现，用 EGCG 处理 A431 和 SCC13 人皮肤癌细胞系会导致细胞活力降低和细胞死亡增加，并且这些细胞毒性作用与β-连环蛋白信号的失活有关。EGCG 诱导的β-连环蛋白失活的证据包括：（i）核β-连环蛋白积累减少；（ii）酪蛋白激酶 1α 水平升高，糖原合酶激酶-3β 磷酸化减少，β-连环蛋白在关键丝氨酸（45,33/37）残基上的磷酸化增加；和（iii）基质金属蛋白酶（MMP）-2 和 MMP-9 的水平降低，β-连环蛋白的下游靶标。用前列腺素 E2（PGE2）处理细胞会增强β-连环蛋白的积累并增强β-连环蛋白信号。用 EGCG 或 EP2 拮抗剂（AH6809）处理可降低 PGE2 增强的β-连环蛋白上游调节因子 cAMP 的水平。EGCG 对β-连环蛋白的失活导致细胞存活信号蛋白的抑制。A431 和 SCC13 细胞中β-连环蛋白的 siRNA 敲低降低了细胞活力。总的来说，这些数据表明，EGCG 诱导皮肤癌细胞的细胞毒性是通过靶向β-连环蛋白信号介导的，而β-连环蛋白信号是由炎症介质上调的。
