Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells
Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells
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DOI：
10.1016/s0003-9861(02)00668-9
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发表时间：
2003-02-01
影响因子：
3.9
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
--
作者：
Gupta, S;Hussain, T;Mukhtar, H
表没食子儿茶素没食子酸酯(EGCG)是绿茶中的主要多酚成分，是一种很有前途的化学预防药物。我们最近在小鼠模型中发现绿茶多酚对前列腺癌有显著的预防作用，其中许多作用是通过多酚诱导癌细胞凋亡的能力来介导的。娜塔莉。阿卡德。SCI。美国98(2001年)10350]。早些时候，我们发现EGCG导致雄激素敏感的LNCaP和雄激素不敏感的DU145细胞的G0/G1期细胞周期停滞和凋亡，与P53状态无关[Toxicol。APPL药水。164(2000)82]。在这里，我们提供了这种效应的分子理解。我们验证了一种假说，即EGCG介导的细胞周期失调和细胞凋亡是通过细胞周期蛋白激酶抑制物(CKI)-细胞周期蛋白依赖性蛋白激酶(CDK)机制来调节的。免疫印迹分析显示，EGCG处理LNCaP和DU145细胞后，WAF1/p21、KIP1/p27、INK4a/p16和INK4c/p18的蛋白表达显著上调，(Ii)细胞周期蛋白D1、细胞周期蛋白E、CDK2、CDK4和CDK6的蛋白表达下调，但不影响细胞周期蛋白D2的表达，(Iii)细胞周期蛋白D1与WAF1/p21和KIP1/p27的结合增加，以及细胞周期蛋白E与CDK2的结合减少。综上所述，我们的结果表明，EGCG引起G1期CKI的诱导，从而抑制作用于细胞周期G0/G1期的Cyclin-cdk复合体，从而导致细胞停滞，这可能是一个最终导致细胞凋亡的不可逆转的过程。这是首次系统研究了CDK抑制剂-细胞周期蛋白-CDK机制的各个组成部分在EGCG诱导的人前列腺癌细胞周期停滞和凋亡过程中的作用。(C)2002年埃尔塞维尔科学公司(美国)。版权所有。
Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG. (C) 2002 Elsevier Science (USA). All rights reserved.