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

So Young Hwang, Xianming Deng, Sanguine Byun, Chan Lee, Seung Joo Lee, Hyunsuk Suh, Jianming Zhang, Qiaofeng Kang, Ting Zhang, Kenneth D. Westover, Anna Mandinova, Sam W. Lee

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26 Citations (Scopus)

Abstract

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, 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/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 therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

Original languageEnglish
Pages (from-to)28-36
Number of pages9
JournalCell Reports
Volume16
Issue number1
DOIs
Publication statusPublished - 2016 Jun 28

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hwang, S. Y., Deng, X., Byun, S., Lee, C., Lee, S. J., Suh, H., Zhang, J., Kang, Q., Zhang, T., Westover, K. D., Mandinova, A., & Lee, S. W. (2016). Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. Cell Reports, 16(1), 28-36. https://doi.org/10.1016/j.celrep.2016.05.071