ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells.
ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells.
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ERRα 抑制增强了 MEK 抑制剂曲美替尼 (Trametinib) 对结肠癌细胞的细胞毒性。
DOI：
10.1186/s13046-018-0862-8
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发表时间：
2018-09-05
期刊：
影响因子：
--
通讯作者：
Bi F
中科院分区：
文献类型：
--
作者：
Zhou S;Xia H;Xu H;Tang Q;Nie Y;Gong QY;Bi F
ERRα是一种调节能量代谢的组成型转录因子，在各种肿瘤的进展中起重要作用。然而，它在细胞存活和增殖中的作用及其在结肠癌靶向治疗中的意义尚不清楚。western blot和免疫组化检测ERRα在结肠癌组织和细胞系中的表达。采用伤口愈合试验和transwell试验检测结肠癌细胞的迁移和侵袭。采用细胞活力实验、克隆实验、western blot和双荧光素酶报告基因实验研究了曲美替尼（MEK抑制剂）与EGF的相互作用。通过流式细胞术、western blotting、定量逆转录聚合酶链反应和异种移植物研究来确定曲美替尼与辛伐他汀联用是否具有协同作用。ERRα正调控结肠癌细胞的增殖、迁移和侵袭，抑制ERRα完全降低EGF诱导的结肠癌细胞增殖。进一步研究发现，曲美替尼部分抑制了EGF诱导的ERRα上调，ERRα抑制增加了结肠癌细胞对曲美替尼的敏感性。最后，我们将曲美替尼与辛伐他汀联合使用，辛伐他汀是一种临床常用的药物，具有抑制ERRα转录活性的新功能，我们发现这种联合在体外和体内都能产生协同作用，抑制结肠癌细胞的增殖和存活。目前的数据表明，ERRα在结肠癌细胞中具有致癌基因的作用，ERRα和MEK的联合靶向治疗可能是一种很有前景的结肠癌治疗策略。本文的在线版本（10.1186/s13046-018-0862-8）包含补充资料，授权用户可使用。
ERRα, a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours. However, its role in cell survival and proliferation and its implication in targeted therapy in colon cancer remains elusive. The expression of ERRα in colon cancer tissues and cell lines was detected by using western blotting and immunohistochemistry. A wound healing assay and a transwell assay were performed to examine the migration and invasion of the colon cancer cells. A cell viability assay, clonogenic assay, western blot assay and the dual-luciferase reporter assay were employed to study the interaction between trametinib (inhibitor of MEK) and EGF treatment. Flow cytometry, western blotting, quantitative reverse-transcription polymerase chain reaction and xenograft studies were used to identify whether the combination of trametinib and simvastatin had a synergistic effect. ERRα positively regulated the cell proliferation, migration and invasion of colon cancer cells, and the suppression of ERRα completely reduced the EGF treatment-induced proliferation of colon cancer cells. Further investigation showed that trametinib partially restrained the up-regulation of ERRα induced by the EGF treatment, and ERRα inhibition increased the sensitivity of colon cancer cells to trametinib. At last, we combined trametinib with simvastatin, a common clinically used drug with a new reported function of transcriptional activity inhibition of ERRα, and found that this combination produced a synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as in vivo. The present data indicated that ERRα acted as an oncogene in colon cancer cells, and the combined targeting of ERRα and MEK might be a promising therapeutic strategy for colon cancer treatment. The online version of this article (10.1186/s13046-018-0862-8) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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发表时间：
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