Moses Michael A, Henry Ellen C, Ricke William A, Gasiewicz Thomas A
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
Cancer Prev Res (Phila). 2015 Mar;8(3):249-57. doi: 10.1158/1940-6207.CAPR-14-0224. Epub 2015 Jan 20.
(-)-Epigallocatechin gallate (EGCG), a major tea polyphenol, elicits anticancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We used nontumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer progression model to test the hypotheses that certain stages are more or less sensitive to EGCG and that sensitivity is related to HSP90 inhibition. Treatment of cells with EGCG, novobiocin, or 17-AAG resulted in more potent cytotoxic effects on tumorigenic and metastatic cells than NT cells. When tumorigenic or metastatic cells were grown in vivo, mice supplemented with 0.06% EGCG in drinking water developed significantly smaller tumors than untreated mice. Furthermore, EGCG prevented malignant transformation in vivo using the full prostate cancer model. To elucidate the mechanism of EGCG action, we performed binding assays with EGCG-Sepharose, a C-terminal HSP90 antibody, and HSP90 mutants. These experiments revealed that EGCG-Sepharose bound more HSP90 from metastatic cells compared with NT cells and binding occurred through the HSP90 C-terminus. In addition, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, novobiocin, and 17-AAG induced changes in HSP90-client proteins in NT cells and larger differences in metastatic cells. These data suggest that EGCG may be efficacious for the treatment of prostate cancer because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype.
（-）-表没食子儿茶素没食子酸酯（EGCG）是一种主要的茶多酚，具有抗癌作用。然而，其作用机制尚未完全明确。我们实验室之前发现EGCG可抑制热休克蛋白90（HSP90）。我们利用一种新型人类前列腺癌进展模型中的非致瘤性（NT）、致瘤性和转移性癌细胞，来验证某些阶段对EGCG的敏感性更高或更低，且敏感性与HSP90抑制相关的假设。用EGCG、新生霉素或17-AAG处理细胞，与NT细胞相比，对致瘤性和转移性细胞产生了更强的细胞毒性作用。当致瘤性或转移性细胞在体内生长时，饮用水中添加0.06% EGCG的小鼠所形成的肿瘤明显小于未处理的小鼠。此外，EGCG利用完整的前列腺癌模型在体内预防了恶性转化。为阐明EGCG的作用机制，我们用EGCG-琼脂糖、HSP90 C端抗体和HSP90突变体进行了结合试验。这些实验表明，与NT细胞相比，EGCG-琼脂糖与转移性细胞中的HSP90结合更多，且结合通过HSP90 C端发生。此外，EGCG与模拟结合态和未结合态HSP90的HSP90突变体结合。与HSP90抑制活性一致，EGCG、新生霉素和17-AAG在NT细胞中诱导了HSP90客户蛋白的变化，在转移性细胞中差异更大。这些数据表明，EGCG可能对前列腺癌治疗有效，因为它优先靶向癌细胞并抑制支持恶性表型的分子伴侣。
