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A Small Molecule Inhibitor of the ?-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo.

ABSTRACT: Colorectal cancer is associated with aberrant activation of the Wnt pathway. ?-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited ?-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on ?-catenin. The formation of the ?-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with ?-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of ?-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of ?-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the ?-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer.

SUBMITTER: Shin SH 

PROVIDER: S-EPMC5704052 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo.

Shin Seung Ho SH   Lim Do Young DY   Reddy Kanamata K   Malakhova Margarita M   Liu Fangfang F   Wang Ting T   Song Mengqiu M   Chen Hanyong H   Bae Ki Beom KB   Ryu Joohyun J   Liu Kangdong K   Lee Mee-Hyun MH   Bode Ann M AM   Dong Zigang Z  

EBioMedicine 20170927

Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formatio  ...[more]

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