Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein
Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein
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通过靶向HuR蛋白发现艾曲波帕在乳腺癌中的抗血管生成作用
DOI：
10.1016/j.apsb.2020.02.007
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Jiange Zhang
中科院分区：
文献类型：
--
作者：
Yuying Zhu;liu qing yang;Jiazhen Xu;Xi-yan Yang;Pengwei Luan;Qianfei Cui;Pei Zhang;Feiyun Wang;Ruixiang Li;Xinyue Ding;Lixian Jiang;Guoqiang Lin;Jiange Zhang
HuR（人类抗原 R）是一种 mRNA 结合蛋白，导致几乎所有类型的恶性肿瘤预后不良，是药物开发的潜在抗肿瘤靶点。在利用基于荧光偏振（FP）的高通量筛选（HTS）系统筛选HuR抑制剂时，鉴定出了临床使用的药物艾曲波帕。通过 FP、电泳迁移率变动分析 (EMSA)、模拟对接和表面等离子共振 (SPR) 验证艾曲波帕在分子水平上的活性。此外，我们还发现艾曲波帕可抑制多种癌细胞系和巨噬细胞的体外细胞增殖，并且在 4T1 荷瘤小鼠模型中也证明了其体内抗肿瘤活性。体内数据表明艾曲波帕可有效减少肿瘤组织中的微血管。然后，我们通过 qRT-PCR、HuR 过表达和 HuR 沉默测定、RNA 稳定性测定、RNA 免疫沉淀和荧光素酶测定证实了艾曲波帕在 4T1 细胞和 RAW264.7 巨噬细胞中的 HuR 依赖性抗血管生成作用。最后，我们通过细胞划痕实验和体外基质胶血管生成实验分析了艾曲波帕对巨噬细胞介导的人脐静脉内皮细胞（HUVEC）的体外抗血管生成作用。通过这些数据，我们揭示了艾曲波帕在乳腺肿瘤中的HuR依赖性抗血管生成作用，表明现有药物艾曲波帕可能作为抗癌药物。
HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibitedin vitrocell proliferation of multiple cancer cell lines and macrophages, and thein vivoanti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. Thein vivodata showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed thein vitroanti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay andin vitroMatrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug.
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DOI：
10.1016/j.apsb.2015.07.008
发表时间：
2015-11
期刊：
Acta pharmaceutica Sinica. B
影响因子：
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作者：
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影响因子：
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影响因子：
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