Novel flexible heteroarotinoid, SL-1-18, promotes ERα degradation to inhibit breast cancer cell growth
Novel flexible heteroarotinoid, SL-1-18, promotes ERα degradation to inhibit breast cancer cell growth
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DOI：
10.1016/j.canlet.2017.08.026
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发表时间：
2017-11-01
期刊：
影响因子：
9.7
通讯作者：
Louie, Maggie C.
中科院分区：
文献类型：
--
作者：
Fallatah, Maryam M.;Liu, Shengquan;Louie, Maggie C.
SL-1-18 (1-(chrysen-6-yl)-3-(4-硝基苯基)硫脲) 是一种新型柔性杂芳香族酸 (Flex-Het) 类似物，源自母体化合物 SHetA2，我们之前的研究表明，在抑制 ER+ 乳腺癌细胞生长方面，其活性与 SHetA2 相当。本研究旨在确定 SL-1-18 对乳腺癌细胞生长影响的分子机制。我们的结果表明，SL-1-18 通过阻止细胞周期进展来抑制 ER+ 乳腺癌细胞（MCF-7 和 T-47D）的细胞增殖。 SL-1-18 治疗与关键细胞周期调节因子（如细胞周期蛋白 D1）以及其他 ER α 靶基因在转录物和蛋白质水平上的表达下降呈正相关。有趣的是，还观察到 ER α 表达下降，SL-1-18 处理后 2 小时内蛋白质水平显着下降，而 mRNA 下降发生在较晚的时间点。 ER α 降解被证明是由泛素化蛋白酶体途径介导的。总之，这是第一项研究表明 Flex-Het-SL-1-18-可以通过泛素-蛋白酶体途径促进 ER α 的降解，应该进一步开发为 ER+ 乳腺癌的治疗选择。 (C) 2017 Elsevier B.V. 保留所有权利。
SL-1-18 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea) is new flexible heteroarotinoid (Flex-Het) analog derived from the parent compound, SHetA2, and our previous study showed comparable activity to SHetA2 in terms of inhibiting ER+ breast cancer cell growth. This current study aims to determine the molecular mechanism underlying SL-1-18's effect on breast cancer cell growth. Our results indicate that SL-1-18 inhibits cell proliferation of ER+ breast cancer cells (MCF-7 and T-47D) by preventing cell cycle progression. SL-1-18 treatment correlated positively with decreased expression of key cell-cycle regulators, such as cyclin D1, as well as other ER alpha-target genes at both the transcript and protein levels. Interestingly, decreased expression of ER alpha was also observed, with a significant reduction at the protein level within 2 h of SL-1-18 treatment, while the decrease in mRNA occurred at a later time point. ER alpha degradation was shown to be mediated by the ubiquitination-proteasome pathway. In summary, this is the first study to show that a Flex-Het-SL-1-18-can promote the degradation of ER alpha via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer. (C) 2017 Elsevier B.V. All rights reserved.