Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA 94901, USA.
College of Pharmacy, Touro University of California, 1310 Club Drive, Vallejo, CA 94594, USA.
Cancer Lett. 2017 Nov 1;408:82-91. doi: 10.1016/j.canlet.2017.08.026. Epub 2017 Aug 25.
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 ERα-target genes at both the transcript and protein levels. Interestingly, decreased expression of ERα 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. ERα 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 ERα via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer.
SL-1-18（1-（金雀花-6-基）-3-（4-硝基苯基）硫脲）是一种新的柔性杂芳基替莫唑胺（Flex-Het）类似物，由母体化合物 SHetA2 衍生而来，我们之前的研究表明，它在抑制 ER+乳腺癌细胞生长方面与 SHetA2 具有相当的活性。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程来抑制 ER+乳腺癌细胞（MCF-7 和 T-47D）的增殖。SL-1-18 处理与关键细胞周期调节剂（如 cyclin D1）以及转录和蛋白质水平上的其他 ERα 靶基因的表达下调呈正相关。有趣的是，还观察到 ERα 表达下调，在 SL-1-18 处理后 2 小时内蛋白水平显著降低，而 mRNA 的减少发生在稍后的时间点。ERα 的降解被证明是由泛素蛋白酶体途径介导的。总之，这是第一项表明 Flex-Het-SL-1-18 能够通过泛素蛋白酶体途径促进 ERα 降解的研究，应该进一步开发作为 ER+乳腺癌的治疗选择。
