Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells.,Cancer Medicine

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Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells.
Cancer Medicine ( IF 2.9 ) Pub Date : 2018-11-18 , DOI: 10.1002/cam4.1877
Wataru Kakuguchi ₁ , Takao Nomura ₂ , Tetsuya Kitamura ₃ , Satoko Otsuguro ₂ , Kazuhiro Matsushita ₁ , Masahiro Sakaitani ₂ , Katsumi Maenaka ₂ , Kanchu Tei ₁

Affiliation

AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin-related genes, and growth factors. HuR binds and stabilizes ARE-mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR-targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration-dependent manner were selected by DSF. Of them, suramin, an anti-trypanosomal drug, binds to HuR, exhibiting fast-on and fast-off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.

中文翻译：

从批准的药物库中筛选出的苏拉明可抑制HuR功能并减弱口腔癌细胞的恶性表型。

富含AU的元件（ARE）存在于从细胞生长相关基因（如原癌基因，细胞周期蛋白相关基因和生长因子）转录的mRNA的3'非翻译区中。HuR结合并稳定ARE-mRNA。HuR在癌细胞和相关的恶性表型中大量表达。HuR基因敲低减弱了口腔癌细胞的恶性表型。在这项研究中，我们通过差示扫描荧光法（DSF）在批准的药物库中筛选了1570种化合物，以发现靶向HuR的化合物。首先，通过DSF选择了55种化合物。然后，通过DSF选择了8种以浓度依赖性方式表现出熔融温度值变化的化合物。其中，苏拉明（一种抗锥虫药物）与HuR结合，在表面等离振子共振（SPR）上表现出快速启动和快速关闭的动力学行为。我们证实，苏拉明可显着降低细胞周期蛋白A2和细胞周期蛋白B1的mRNA和蛋白表达。苏拉明使细胞周期蛋白A2和细胞周期蛋白B1 mRNA不稳定。此外，用苏拉明处理的舌癌细胞系的运动和侵袭活性明显低于对照细胞。上述发现表明苏拉明与HuR结合并抑制其功能。我们还显示了苏拉明的抗癌作用是由抑制HuR功能引起的，表明其在口腔癌治疗中作为一种新型治疗剂的潜力。我们的结果表明，苏拉明通过其不同的机制可以有效抑制无法使用其他抗癌药控制的进行性口腔癌。苏拉明使细胞周期蛋白A2和细胞周期蛋白B1 mRNA不稳定。此外，苏拉明处理的舌癌细胞系的运动和侵袭活性明显低于对照细胞。上述发现表明苏拉明与HuR结合并抑制其功能。我们还显示了苏拉明的抗癌作用是由抑制HuR功能引起的，表明其在口腔癌治疗中作为一种新型治疗剂的潜力。我们的结果表明，苏拉明通过其不同的机制可以有效抑制无法使用其他抗癌药控制的进行性口腔癌。苏拉明使细胞周期蛋白A2和细胞周期蛋白B1 mRNA不稳定。此外，用苏拉明处理的舌癌细胞系的运动和侵袭活性明显低于对照细胞。上述发现表明苏拉明与HuR结合并抑制其功能。我们还显示了苏拉明的抗癌作用是由抑制HuR功能引起的，表明其在口腔癌治疗中作为一种新型治疗剂的潜力。我们的结果表明，苏拉明通过其不同的机制可以有效抑制无法使用其他抗癌药控制的进行性口腔癌。上述发现表明苏拉明与HuR结合并抑制其功能。我们还显示了苏拉明的抗癌作用是由抑制HuR功能引起的，表明其在口腔癌治疗中作为一种新型治疗剂的潜力。我们的结果表明，苏拉明通过其不同的机制可以有效抑制无法使用其他抗癌药控制的进行性口腔癌。上述发现表明苏拉明与HuR结合并抑制其功能。我们还显示了苏拉明的抗癌作用是由抑制HuR功能引起的，表明其在口腔癌治疗中作为一种新型治疗剂的潜力。我们的结果表明，苏拉明通过其不同的机制可以有效抑制无法使用其他抗癌药控制的进行性口腔癌。

更新日期：2018-11-20

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