Wnt信号通路
大肠腺瘤性息肉病
癌症研究
结直肠癌
连环素
转录因子
细胞生长
癌症
细胞周期
连环蛋白
信号转导
化学
细胞生物学
生物
医学
内科学
基因
生物化学
作者
Yu Yan,Yidan Zhang,Mengyuan Li,Yazhou Zhang,Xinxin Zhang,Xiaonan Zhang,Yuting Xu,Wei Wei,Jie Wang,Xiaohan Xu,Qiaoling Song,Chenyang Zhao
出处
期刊:Cancer Science
[Wiley]
日期:2021-09-12
卷期号:112 (11): 4722-4735
被引量:4
摘要
Abstract The Wnt/β‐catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid‐enhancing factor (LEF) luciferase reporter system, the high‐throughput screening of 18 840 small‐molecule compounds was performed. A novel scaffold compound, C644‐0303, was identified as a Wnt/β‐catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644‐0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644‐0303 could suppress various tumor‐promoting transcription factor activities in addition to Wnt/β‐catenin. Finally, C644‐0303 suppressed tumor spheroidization in a 3‐dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/β‐catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.
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