通过下调FOXM1的新型小分子抑制剂1-3-51抗胃癌细胞的作用

Anti-gastric cancer effect of a novel small molecule inhibitor 1-3-51 targeting FOXM1 in vitro

目的研究新型小分子抑制剂1-3-51在胃癌中调控FOXM1(Forkhead box protein M1)表达及其抗癌的作用。方法CCK-8实验检测1-3-51处理后的BGC823和MKN45细胞IC_(50);Western blot检测胃癌细胞FOXM1表达;qRT-PCR检测胃癌细胞FOXM1及其下游分子Cyclin D1和MMP9 mRNA表达;流式细胞术测定细胞周期情况;Transwell实验检测胃癌细胞迁移和侵袭能力;裸鼠皮下移植瘤模型检测1-3-51抗胃癌增殖效果;在胃癌细胞BGC823中转染FOXM1过表达质粒及其空载质粒,CCK-8实验、Transwell实验分别检测1-3-51对胃癌细胞活性、迁移及侵袭等的影响。结果新型小分子抑制剂1-3-51在BGC823和MKN45细胞作用48 h后的IC_(50)分别为(5.429±0.225)μmol/L、(5.169±0.239)μmol/L,并可以显著抑制FOXM1的表达及其下游分子Cyclin D1和MMP9 mRNA表达。1-3-51显著抑制胃癌细胞的增殖、侵袭及迁移。过表达FOXM1后,可部分逆转其抑制细胞增殖、侵袭及迁移能力。结论小分子抑制剂1-3-51在胃癌细胞中可通过抑制FOXM1及其下游分子Cyclin D1和MMP9等的表达,进而降低胃癌细胞增殖、迁移、侵袭能力。

Objective To investigate the role of a novel small molecule inhibitor 1-3-51 in the regulation of FOXM1 expression and its anticancer effect in gastric cancer.Methods CCK-8 assay was employed to measure the IC_(50) values in gastric cancer BGC823 and MKN45 cells after 1-3-51 treatment.Western blotting was used to detect FOXM1 expression in the cells.qRT-PCR was adopted to study the mRNA expression of FOXM1 and its downstream target genes Cyclin D1 and MMP9.Flow cytometry and Transwell assay were applied respectively to determine the cell cycle and the migration and invasion of the cells.The anti-proliferation effect of 1-3-51 on gastric cancer was detected in xenograft nude mouse model.FOXM1 overexpression plasmid and the corresponding control vector were transfected into gastric cancer cells BGC823 respectively.CCK-8 assay and Transwell assay were used to detect the changes of 1-3-51 on the activity,migration and invasion of gastric cancer cells.Results The IC_(50) values of BGC823 and MKN45 cells to 1-3-51 treatment for 48 h was 5.429±0.225 and 5.169±0.239μmol/L,respectively.And the treatment resulted in significantly decreased expression of FOXM1 and its downstream molecules Cyclin D1 and MMP9.The treatment also significantly suppressed the proliferation,invasion and migration of the gastric cancer cells.Overexpression of FOXM1 partially reversed its abilities to inhibit cell proliferation,invasion and migration.Conclusion Our small molecule inhibitor,1-3-51,can suppress the expression of FOXM1 and its downstream target molecules Cyclin D1 and MMP9 in gastric cancer cells,and thereby reduce the proliferation,migration and invasion abilities of the cells.