Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

被引：112

作者：

Hwang, So-Young ^{[1
,2
]}

Deng, Xianming ^{[3
]}

Byun, Sanguine ^{[1
,2
]}

Lee, Chan ^{[1
,2
]}

Lee, Seung-Joo ^{[4
]}

Suh, Hyunsuk ^{[4
]}

Zhang, Jianming ^{[1
,2
]}

Kang, Qiaofeng ^{[3
]}

Zhang, Ting ^{[3
]}

Westover, Kenneth D. ^{[5
]}

Mandinova, Anna ^{[1
,2
,6
]}

Lee, Sam W. ^{[1
,2
,6
]}

机构：

[1] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA

[2] Harvard Med Sch, Charlestown, MA 02129 USA

[3] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China

[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Biochem & Radiat Oncol, Dallas, TX 75390 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 01期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

CANCER-CELLS; WNT PATHWAY; FUNCTIONAL INTERACTION; XENOPUS EMBRYOS; HIGH-FREQUENCY; COLON-CANCER; TCF COMPLEX; ACTIVATION; TRANSCRIPTION; INHIBITION;

D O I：

10.1016/j.celrep.2016.05.071

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The Wnt/beta-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of beta-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic beta-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/beta-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl) sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/beta-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to beta-catenin, promoting its degradation, and specifically downregulates Wnt/beta-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/beta-catenin signaling pathway.

引用

页码：28 / 36

页数：9

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