Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents
Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents
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DOI：
10.1016/s0006-2952(00)00385-3
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发表时间：
2000-10-15
影响因子：
5.8
通讯作者：
Agarwal, R
中科院分区：
文献类型：
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作者：
Agarwal, R
前列腺癌（PCA）是最常见的侵袭性恶性肿瘤，也是男性癌症死亡的主要原因（仅次于肺癌）。由于PCA最初是雄激素依赖性的，因此策略的目标是控制雄激素消耗。然而，肿瘤再生长主要发生在这种模式之后，并且是雄激素非依赖性的。功能性雄激素受体的丧失和生长因子受体（例如erbB家族成员）和相关配体的表达增强已被证明是PCA进展中的因果遗传事件。这些遗传改变导致表观遗传机制，其中膜受体（例如表皮生长因子受体[erbB 1]）和相关配体（例如转化生长因子-α）之间的反馈自分泌回路导致细胞外信号调节蛋白激酶1/2（ERK 1/2）的活化增强，ERK 1/2是晚期和雄激素非依赖性阶段PCA不受控制生长的重要组成部分。总之，我们合理地认为，抑制这些表观遗传事件将有助于控制先进的PCA的增长。膳食多酚类黄酮和黄酮类化合物作为癌症预防和干预剂正在被广泛研究。因此，我们把我们的注意力集中在水飞蓟素，染料木素和表没食子儿茶素3-没食子酸酯（EGCG），目前在奶蓟，集。豆类和绿色茶。评价这些药物对erbB 1-Shc-ERK 1/2信号转导通路、细胞周期调节分子和细胞生长与死亡的影响。在雄激素非依赖性人前列腺癌DU145细胞中，水飞蓟素、染料木素和表没食子酸没食子酸酯导致转化生长因子-α引起的膜受体erbB1活化的显著至完全抑制，随后抑制下游细胞质信号传导靶点Shc活化并降低其与erbB1的结合，而不改变其蛋白质表达。水飞蓟素和染料木黄酮也抑制ERK 1/2激活，表明这些药物损害DU145细胞中erbB1-Shc-ERK 1/2信号转导的激活。在EGCG的情况下，观察到ERK 1/2活化的进一步增加，这与其促氧化和凋亡活性有关。水飞蓟素、染料木素和EGCG也导致Cip1/p21和Kip1/p27的显著诱导和细胞周期蛋白依赖性激酶（CDK）4的减少，但观察到CDK2、细胞周期蛋白D1和细胞周期蛋白E的中度抑制。Cip1/p21和Kip1/27水平的提高也导致其与CDK4和CDK2的结合增加。用水飞蓟素、染料木素和EGCG处理细胞也在较低剂量下导致强烈的细胞生长抑制，并且在较高剂量下导致完全抑制。与水飞蓟素相反，较高剂量的染料木黄酮也显示细胞死亡。在EGCG的情况下观察到更深刻的细胞毒性作用，在较低剂量下具有强烈的细胞死亡，在较高剂量下完全丧失活力。总之，这些结果表明，细胞信号传导和细胞周期的调节剂是通过饮食剂预防前列腺癌的潜在表观遗传分子靶点。因此，需要对这些药物进行更多的研究，以探索其对人类前列腺癌的抗癌潜力。生物化学制药60; 8：1051 - 1059，2000年。(C)2000 Elsevier Science Inc.
Prostate cancer (PCA) is the most common invasive malignancy and leading cause (after lung) of cancer deaths in males. Since PCA is initially androgen-dependent, strategies are targeted toward androgen depletion fur its control. However, tumor regrowth mostly occurs following this modality, and is androgen independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and associated ligands have been shown to he the causal genetic events in PCA progression. These genetic alterations lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptor (e.g. epidermal growth factor receptor [erbB1] and associated ligand (e.g. transforming growth factor-alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we rationalized that inhibiting these epigenetic events would be useful in controlling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavones are being studied extensively as cancer preventive and interventive agents. Therefore, we focused our attention on silymarin, genistein, and epigallocatechin 3-gallate (EGCG), present in milk thistle, set. beans, and green tea, respectively. nle effect of these agents was assessed on the erbB1-Shc-ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and cell growth and death. In androgen-independent human prostate carcinoma DU145 cells, silymarin, genistein, and EGCG resulted in a significant to complete inhibition of transforming growth factor-alpha-caused activation of membrane receptor erbB1 followed by inhibition of downstream cytoplasmic signaling target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also inhibited ERK1/2 activation, suggesting that these agents impair the activation of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a further increase in ERK1/2 activation was observed that was related to its pro-oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resulted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein also showed cell death. A more profound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Together, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer. BIOCHEM PHARMACOL 60;8:1051-1059, 2000. (C) 2000 Elsevier Science Inc.