Novel small molecule inhibitors of the transcription factor ETS-1 and their antitumor activity against hepatocellular carcinoma
Novel small molecule inhibitors of the transcription factor ETS-1 and their antitumor activity against hepatocellular carcinoma
复制标题
DOI：
10.1016/j.ejphar.2021.174214
复制
发表时间：
2021-06-14
影响因子：
5
通讯作者：
Gu, Anxin
中科院分区：
文献类型：
--
作者：
Jie, Yamin;Liu, Guijun;Gu, Anxin
转录因子Ets-1(E26转换特异性序列1)是恶性肿瘤细胞增殖和侵袭的关键调控因子，通过调节基质金属蛋白酶等侵袭/迁移相关因子的转录。本工作旨在利用小分子化合物文库筛选新的ETS-1小分子抑制剂，并研究其抗肝细胞癌的活性。该荧光素酶报告用于检测Ets-1‘S转录因子活性在肝癌细胞中的抑制和激活情况，该细胞包括高侵袭性肝癌细胞系MHCC97-H和五个患者来源的细胞系。用四甲基偶氮唑盐比色法检测对肝癌细胞增殖的抑制作用，用Transwell法检测肝癌细胞的侵袭力。所选化合物对肝癌细胞的抗肿瘤活性也在裸鼠皮下肿瘤模型或肝内肿瘤模型中进行了检测。结果表明，首次发现与EI-4相似的4个化合物EI1能够抑制Ets-1转录因子的激活和抑制肝癌细胞的增殖或侵袭。四种化合物中，EI-4的活性最强。本文的研究结果有助于扩大我们对ETS-1的认识，并为我们提供更安全、更有效的肝癌分子治疗策略。
The transcription factor ETS-1 (E26 transformation specific sequence 1) is the key regulator for malignant tumor cell proliferation and invasion by mediating the transcription of the invasion/migration related factors, e.g. MMPs (matrix metalloproteinases). This work aims to identify the novel small molecule inhibitors of ETS-1 using a small molecule compound library and to study the inhibitors' antitumor activity against hepatocellular carcinoma (HCC). The luciferase reporter is used to examine the inhibition and activation of ETS-1's transcription factor activity in HCC cells, including a highly invasive HCC cell line, MHCC97-H, and five lines of patient-derived cells. The inhibition of the proliferation of HCC cells is examined using the MTT assay, while the invasion of HCC cells is examined using the transwell assay. The anti-tumor activity of the selected compound on HCC cells is also examined in a subcutaneous tumor model or intrahepatic tumor model in nude mice. The results show that for the first time, four compounds, EI1 similar to EI-4, can inhibit the transcription factor activation of ETS-1 and the proliferation or invasion of HCC cells. Among the four compounds, EI-4 has the best activation. The results from this paper contribute to expanding our understanding of ETS-1 and provide alternative, the safer and more effective, HCC molecular therapy strategies.