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

Research output: Contribution to journalArticle

16 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 (US)
Pages (from-to)28-36
Number of pages9
JournalCell Reports
Volume16
Issue number1
DOIs
StatePublished - Jun 28 2016

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Catenins
Degradation
Molecules
Benzoates
Neoplasms
Wnt Signaling Pathway
Tissue homeostasis
TCF Transcription Factors
Human Development
Luciferases
Tumors
Homeostasis
Down-Regulation
Genes
Chemical activation
Cells
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. / Hwang, So Young; Deng, Xianming; Byun, Sanguine; Lee, Chan; Lee, Seung Joo; Suh, Hyunsuk; Zhang, Jianming; Kang, Qiaofeng; Zhang, Ting; Westover, Kenneth D.; Mandinova, Anna; Lee, Sam W.

In: Cell Reports, Vol. 16, No. 1, 28.06.2016, p. 28-36.

Research output: Contribution to journalArticle

Hwang, SY, Deng, X, Byun, S, Lee, C, Lee, SJ, Suh, H, Zhang, J, Kang, Q, Zhang, T, Westover, KD, Mandinova, A & Lee, SW 2016, 'Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling', Cell Reports, vol. 16, no. 1, pp. 28-36. https://doi.org/10.1016/j.celrep.2016.05.071
Hwang, So Young ; Deng, Xianming ; Byun, Sanguine ; Lee, Chan ; Lee, Seung Joo ; Suh, Hyunsuk ; Zhang, Jianming ; Kang, Qiaofeng ; Zhang, Ting ; Westover, Kenneth D. ; Mandinova, Anna ; Lee, Sam W. / Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. In: Cell Reports. 2016 ; Vol. 16, No. 1. pp. 28-36.
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