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

被引：30
作者：
Kakuguchi, Wataru [1 ,2 ]
Nomura, Takao [3 ]
Kitamura, Tetsuya [2 ,4 ]
Otsuguro, Satoko [3 ]
Matsushita, Kazuhiro [1 ,2 ]
Sakaitani, Masahiro [3 ]
Maenaka, Katsumi [3 ]
Tei, Kanchu [1 ,2 ]
机构：
[1] Hokkaido Univ, Fac Dent Med, Dept Oral & Maxillofacial Surg, Sapporo, Hokkaido, Japan
[2] Hokkaido Univ, Grad Sch Dent Med, Sapporo, Hokkaido, Japan
[3] Hokkaido Univ, Fac Pharmaceut Sci, Ctr Res & Educ Drug Discovery, Sapporo, Hokkaido, Japan
[4] Hokkaido Univ, Dept Oral Pathol & Biol, Fac Dent Med, Sapporo, Hokkaido, Japan
来源：
CANCER MEDICINE | 2018年 / 7卷 / 12期
基金：
日本学术振兴会;
关键词：
AU-rich elements; drug repositioning; HuR; screening; suramin; MESSENGER-RNA STABILITY; BINDING PROTEIN HUR; AU-RICH ELEMENTS; LIGAND INTERACTIONS; EXPRESSION; GROWTH; ELAV; PHOSPHORYLATION; IDENTIFICATION; TRANSLATION;
D O I：
10.1002/cam4.1877
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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.
引用
收藏
页码：6269 / 6280
页数：12
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