Green tea polyphenol, (-)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting β-catenin signaling.
Green tea polyphenol, (-)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting β-catenin signaling.
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DOI：
10.1016/j.taap.2013.09.021
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发表时间：
2013-12-01
影响因子：
3.8
通讯作者：
Katiyar, Santosh K.
中科院分区：
文献类型：
--
作者：
Singh, Tripti;Katiyar, Santosh K.
关键词：
绿色茶多酚（-）-表没食子儿茶素-3-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，并且正在继续努力研究负责其细胞毒性作用的分子靶点对癌细胞。我们最近观察到β-catenin在皮肤肿瘤中上调，这表明EGCG的抗皮肤致癌作用可能至少部分是通过其对β-catenin信号传导的影响介导的。我们已经发现，用EGCG处理A431和SCC 13人皮肤癌细胞系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-连环蛋白信号转导的失活相关。EGCG诱导的β-连环蛋白失活的证据包括：（i）核β-连环蛋白的积累减少;（ii）酪蛋白激酶1α的水平增加，糖原合成酶激酶-3 β的磷酸化减少，关键丝氨酸45、33/37残基上β-连环蛋白的磷酸化增加;和（iii）基质金属蛋白酶（MMP）-2和MMP-9的水平降低，它们是β-连环蛋白的下游靶点。用前列腺素E2（PGE 2）处理细胞增强了β-连环蛋白的积累并增强了β-连环蛋白信号传导。用EGCG或EP 2拮抗剂（AH 6809）处理降低了PGE 2增强的cAMP水平，cAMP是β-连环蛋白的上游调节剂。EGCG对β-catenin的失活导致细胞存活信号蛋白的抑制。A431和SCC 13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，通过EGCG诱导皮肤癌细胞的细胞毒性是通过靶向β-连环蛋白信号传导介导的，并且β-连环蛋白信号传导被炎性介质上调。
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 kinase 1α, reduced phosphorylation of glycogen synthase kinase-3β, and increased phosphorylation of β-catenin on critical serine45,33/37 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.
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