Compound TI503 Inhibits Breast Cancer Cells Proliferation through Up-regulating the Expression of TSP50-targeting miR-937-5p and miR-4709-3p

【作者】 王丹凤； 鲍永利； 李玉新；

【机构】 东北师范大学药物基因和蛋白筛选国家工程实验室； 东北师范大学遗传与细胞研究所；

【摘要】 Testes-specific protease 50(TSP50), an oncogene is expressed abnormally at high levels inmost cancer tissues and low levels in normal tissues. Down-regulation of TSP50 expressionhas been found to reduce cell proliferation and colony formation, which makes it a potentialtarget for cancer therapy. MicroRNAs can negatively regulate target gene expressionthrough complementarity between the miRNA seed sequence and the target mRNA 3’untranslated region(3’UTR). In this study, we constructed a firefly luciferase-TSP503’UTR reporter(pGL3-TSP50) as the drug screening model to screen the potential candidateanticancer compound from over 600 natural compounds. The result showed thatthe compound TI503 is capable of inhibiting the activity of luciferase and the expression ofTSP50 protein. Further study revealed that TI503 can inhibit MDAMB-231 cell proliferationand induce G2/M phase cell cycle arrest. We next investigated the mechanisms involved inthis process, the results showed that compound TI503 can enhance the expression of endogenousmiR-937-5p and miR-4709-3p. In addition, overexpression of miR-937-5p andmiR-4709-3p mimics inhibited the expression of TSP50 protein, whereas overexpression ofmiR-937-5p and miR-4709-3p inhibitors could enhance the activity of luciferase and theexpression of TSP50 protein. These results suggest that down-regulation of TSP50 expressionmight be a potential approach for anti-cancer drug screening and compound TI503 may become a potent agent for tumor chemotherapy.更多还原

【Abstract】 Testes-specific protease 50(TSP50), an oncogene is expressed abnormally at high levels inmost cancer tissues and low levels in normal tissues. Down-regulation of TSP50 expressionhas been found to reduce cell proliferation and colony formation, which makes it a potentialtarget for cancer therapy. MicroRNAs can negatively regulate target gene expressionthrough complementarity between the miRNA seed sequence and the target mRNA 3’untranslated region(3’UTR). In this study, we constructed a firefly luciferase-TSP503’UTR reporter(pGL3-TSP50) as the drug screening model to screen the potential candidateanticancer compound from over 600 natural compounds. The result showed thatthe compound TI503 is capable of inhibiting the activity of luciferase and the expression ofTSP50 protein. Further study revealed that TI503 can inhibit MDAMB-231 cell proliferationand induce G2/M phase cell cycle arrest. We next investigated the mechanisms involved inthis process, the results showed that compound TI503 can enhance the expression of endogenousmiR-937-5p and miR-4709-3p. In addition, overexpression of miR-937-5p andmiR-4709-3p mimics inhibited the expression of TSP50 protein, whereas overexpression ofmiR-937-5p and miR-4709-3p inhibitors could enhance the activity of luciferase and theexpression of TSP50 protein. These results suggest that down-regulation of TSP50 expressionmight be a potential approach for anti-cancer drug screening and compound TI503 may become a potent agent for tumor chemotherapy.更多还原