Proteasome-independent down-regulation of estrogen receptor-α (ERα) in breast cancer cells treated with 4,4′-dihydroxy-trans-stilbene
Proteasome-independent down-regulation of estrogen receptor-α (ERα) in breast cancer cells treated with 4,4′-dihydroxy-trans-stilbene
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DOI：
10.1016/j.bcp.2006.05.023
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发表时间：
2006-08-28
影响因子：
5.8
通讯作者：
Han, Zhiyong
中科院分区：
文献类型：
--
作者：
Balan, Kannan V.;Wang, Yongbao;Han, Zhiyong
用雌激素和几种纯ER α拮抗剂处理细胞，通过对蛋白酶体抑制剂MG 132和裂乳胞素-β-内酯敏感的机制，迅速诱导细胞核中α型雌激素受体（ER α）的下调。因此，据信这些ER配体通过蛋白酶体依赖性机制诱导ER α的下调，其用于控制细胞中转录活性的量和配体结合的ER α的水平。在这项研究中，我们观察到用低亲和力ER配体4，4 '-二羟基-反式-二苯乙烯（4，4'-DHS）处理培养的MCF 7和T47 D人乳腺癌细胞，抑制ER α的转录活性，并诱导ER α蛋白量缓慢和逐渐减少（下文称为ER α的下调）。MCF-7细胞中4，4 '-DHS诱导的ER α下调涉及一种机制，该机制对两种最具特异性的蛋白酶体抑制剂（裂乳胞素-胎盘素和环氧霉素）不敏感，但对超过MCF-7细胞中蛋白酶体最大抑制所需浓度的MG 132敏感。因此，4，4 '-DHS似乎通过蛋白酶体非依赖性机制诱导ER α下调。在这里，我们提供的数据表明，4-OH和4 '-OH都是4，4'-DHS诱导ER α下调的能力的关键，并表明4，4 '-DHS为开发新的ER α拮抗剂提供了有用的支架。(c)2006爱思唯尔公司All rights reserved.
Treatment of cells with estrogens and several pure ER alpha antagonists rapidly induces down-regulation of the alpha-type estrogen receptor (ERa) in the nucleus by mechanisms that are sensitive to the proteasome inhibitors, MG132 and clasto-lactacystin-beta-lactone. Hence, it is believed that these ER ligands induce down-regulation of ER alpha by proteasome-dependent mechanisms, which serve to control both the amount of transcriptional activity and the level of ligand-bound ER alpha in cells. In this study, we observed that treatment of cultured MCF7 and T47D human breast cancer cells with the low affinity ER ligand, 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), inhibited the transcriptional activity of ER alpha and induced slow and gradual decrease in the amount of ER alpha protein (henceforth referred to as down-regulation of ER alpha). The 4,4'-DHS-induced down-regulation of ER alpha in MCF-7 cells involved a mechanism that was insensitive to the two most specific proteasome inhibitors, clasto-lactacystin-plactone and epoxomycin, but sensitive to MG132 at concentrations exceeding that required for maximal inhibition of the proteasome in MCF-7 cells. Therefore, 4,4'-DHS appears to induce down-regulation of ER alpha by a proteasome-independent mechanism. Here, we present data to show that both 4-OH and 4'-OH are critical for the ability of 4,4'-DHS to induce down-regulation of ER alpha and suggest that 4,4'-DHS provides a useful scaffold for development of novel ER alpha antagonists. (c) 2006 Elsevier Inc. All rights reserved.