Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling.
Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling.
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DOI：
10.1016/j.celrep.2016.05.071
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发表时间：
2016-06-28
期刊：
影响因子：
8.8
通讯作者：
Lee SW
中科院分区：
文献类型：
--
作者：
Hwang SY;Deng X;Byun S;Lee C;Lee SJ;Suh H;Zhang J;Kang Q;Zhang T;Westover KD;Mandinova A;Lee SW
Wnt/β-catenin信号通路在组织稳态中发挥着重要作用，其失调可导致多种人类疾病。 β-连环蛋白的异常激活具有致癌性，是人类癌症发生和进展的关键驱动因素。尽管针对致癌β-连环蛋白途径进行癌症治疗具有巨大潜力，但特异性抑制剂的开发仍然不足。使用 T 细胞因子 (TCF) 依赖性荧光素酶报告基因系统，我们筛选了对抗 Wnt/β-连环蛋白信号传导的小分子化合物，并确定了 MSAB（甲基 3-{[(4-甲基苯基)磺酰基]氨基}苯甲酸酯）作为 Wnt/β-连环蛋白信号传导的选择性抑制剂。 MSAB 在体外和小鼠癌症模型中对 Wnt 依赖性癌细胞具有选择性的有效抗肿瘤作用。 MSAB 与 β-catenin 结合，促进其降解，并特异性下调 Wnt/β-catenin 靶基因。我们的研究结果可能代表了一种针对 Wnt/β-连环蛋白信号通路成瘾的癌症的有效策略。
The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, development of specific inhibitors remains insufficient. Using a T-cell factor (TCF)-dependent luciferase-reporter system, we screen for small molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective strategy for cancers addicted to the Wnt/β-catenin signaling pathway.