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

ABSTRACT: The Wnt/?-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of ?-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic ?-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/?-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/?-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to ?-catenin, promoting its degradation, and specifically downregulates Wnt/?-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/?-catenin signaling pathway.

SUBMITTER: Hwang SY 

PROVIDER: S-EPMC4957947 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature