紫草素调控Wnt/β-catenin抑制腺瘤性结肠息肉突变结肠癌细胞生长
Shikonin Inhibits APC-mutant Colon Cancer via Wnt/β-catenin Signaling
陈黎喆 1王伯军 1龚晴 1张雪 1柯细松1
作者信息
- 1. 201203 上海,上海中医药大学交叉科学研究院化学生物研究中心
- 折叠
摘要
目的 发现腺瘤性结肠息肉(APC)突变结肠癌的小分子抑制剂,为结肠癌靶向治疗提供先导化合物.方法 构建稳定表达7*Tcf-GFP/SV40-Cherry(7TGC)双重荧光报告系统的APC突变结肠癌细胞系用于小分子抑制剂筛选.细胞活力测定、克隆形成、EdU和动物移植瘤实验检测小分子对体内外APC突变结肠癌的抑制作用,免疫印记和免疫共沉淀实验探究其分子机制.结果 发现了4个抑制APC突变结肠癌细胞Wnt活性的小分子,其中紫草素显著抑制APC突变结肠癌的细胞活力和增殖能力并诱导细胞凋亡;移植瘤实验结果表明紫草素显著减缓体内瘤体生长;免疫印记和免疫共沉淀实验进一步发现紫草素可显著减少β-catenin的水平.结论 紫草素可显著抑制APC突变结肠癌的Wnt活性和肿瘤生长.
Abstract
Objective To identify small molecule inhibitors of APC-mutant colon cancer and provide lead compounds for targeted therapy of colon cancer.Methods APC-mutant colon cancer cell lines that stably express 7*Tcf-GFP/SV40-Cherry(7TGC)dual fluorescence reporter system was constructed for small-molecule inhibitor screening.Cell viability,colony formation,EdU incorporation,and xenograft tumor assay were used to evaluate the inhibitory effect of these inhibitors on APC-mutant colon cancer in vitro and in vivo.Western blot and co-immunoprecipitation assays were used to explore the molecular mechanism.Results Four small molecules that inhibited Wnt activity in APC-mutant colon cancer cells were discovered.Shikonin exhibited significant inhibition of cell viability and proliferation while inducing apoptosis of APC-mutant colon cancer cells.Xenograft tumor assay demonstrated that shikonin significantly reduced tumor growth in vivo.Furthermore,Western blot and co-immunoprecipitation assays revealed that shikonin markedly decreased β-catenin levels.Conclusion Shikonin effectively inhibits Wnt activity and suppresses tumor growth in APC-mutant colon cancer.
关键词
APC突变/结肠癌/Wnt/β-catenin信号通路/紫草素Key words
APC mutation/Colon cancer/Wnt/β-catenin signaling/Shikonin引用本文复制引用
基金项目
国家自然科学基金面上项目(82173845)
出版年
2024
国家科技期刊平台
NSTL
万方数据