Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells
Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells
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DOI：
10.1006/taap.1999.8885
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发表时间：
2000-04-01
影响因子：
3.8
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
--
作者：
Gupta, S;Ahmad, N;Mukhtar, H
前列腺癌（PCA）是美国最普遍的癌症，也是男性癌症相关死亡的第二大原因。描述性流行病学数据表明，雄激素和环境暴露在前列腺癌发生中起关键作用。由于雄激素作用与增殖和分化密切相关，在人类临床诊断时，大多数PCA表现为雄激素敏感细胞和雄激素不敏感细胞的混合物。雄激素敏感细胞在雄激素停用后迅速凋亡。另一方面，雄激素不敏感细胞在雄激素阻断后不会发生凋亡，而是维持凋亡的分子机制。因此，能够抑制雄激素敏感细胞和雄激素不敏感细胞生长和/或诱导细胞凋亡的药物将有助于PCA的治疗。在本研究中，我们发现(-)-表没食子儿茶素-3-没食子酸酯（EGCG），绿茶中存在的主要多酚成分，对雄激素敏感和雄激素不敏感的人PCA细胞都具有抗增殖作用，这种作用是通过调节细胞周期和诱导凋亡介导的。在雄激素不敏感的DU145和雄激素敏感的LNCaP细胞中，EGCG治疗可导致剂量依赖性的细胞生长抑制。在这两种细胞类型中，EGCG处理也导致DNA细胞周期分析中观察到的剂量依赖的G(0)/G(1)期细胞周期阻滞。DNA阶梯实验、共聚焦显微镜和流式细胞术表明，EGCG处理DU145和LNCaP细胞均导致剂量依赖性的凋亡。Western blot分析显示，EGCG处理导致(i) LNCaP细胞（携带野生型p53）中p53的剂量依赖性增加，而DU145细胞（携带突变型p53）中p53的剂量依赖性增加，以及（ii）在两种细胞类型中诱导细胞周期蛋白激酶抑制剂WAF1/p21。这些结果表明，EGCG通过影响有丝分裂和诱导细胞凋亡，以细胞类型特异性的方式负调节PCA细胞的生长，这可能是由WAF1/p21介导的G(0)/G(1)期细胞周期阻滞，而与雄激素相关或细胞p53状态无关。(C) 2000年学术出版社。
Prostate cancer (PCA) is the most prevalent cancer diagnosed and the second leading cause of cancer-related deaths among men in the United States. Descriptive epidemiological data suggest that androgens and environmental exposures play a key role in prostatic carcinogenesis. Since androgen action is intimately associated with proliferation and differentiation, at the time of clinical diagnosis in humans most PCA represent themselves as a mixture of androgen-sensitive and androgen-insensitive cells. Androgen-sensitive cells undergo rapid apoptosis upon androgen withdrawal. On the other hand, the androgen-insensitive cells do not undergo apoptosis upon androgen blocking, but maintain the molecular machinery of apoptosis. Thus, agents capable of inhibiting growth and/or inducing apoptosis in both androgen-sensitive and androgen-insensitive cells will be useful for the management of PCA. In the present study, we show that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparts antiproliferative effects against both androgen-sensitive and androgen-insensitive human PCA cells, and this effect is mediated by deregulation in cell cycle and induction of apoptosis. EGCG treatment,vas found to result in a dose-dependent inhibition of cell growth in both androgen-insensitive DU145 and androgen-sensitive LNCaP cells. In both the cell types, EGCG treatment also resulted in a dose-dependent G(0)/G(1)-phase arrest of the cell cycle as observed by DNA cell-cycle analysis. As evident by DNA ladder assay, confocal microscopy, and flow cytometry, the treatment of both DU145 and LNCaP cells with EGCG resulted in a dose-dependent apoptosis. Western blot analysis revealed that EGCG treatment resulted in (i) a dose-dependent increase of p53 in LNCaP cells (carrying wild-type p53), but not in DU145 cells (carrying mutant p53), and (ii) induction of cyclin kinase inhibitor WAF1/p21 in both cell types. These results suggest that EGCG negatively modulates PCA cell growth, by affecting mitogenesis as web as inducing apoptosis, in cell-type-specific manner which may be mediated by WAF1/p21-caused G(0)/G(1)-phase cell-cycle arrest, irrespective of the androgen association or p53 status of the cells. (C) 2000 Academic Press.