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

Seung Ho Shin; Do Young Lim; Kanamata Reddy; Margarita Malakhova; Fangfang Liu; Ting Wang; Mengqiu Song; Hanyong Chen; Ki Beom Bae; Joohyun Ryu; Kangdong Liu; Mee-Hyun Lee; Ann M. Bode; Zigang Dong

doi:10.1016/j.ebiom.2017.09.029

EBioMedicine (Nov 2017)

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

Seung Ho Shin,
Do Young Lim,
Kanamata Reddy,
Margarita Malakhova,
Fangfang Liu,
Ting Wang,
Mengqiu Song,
Hanyong Chen,
Ki Beom Bae,
Joohyun Ryu,
Kangdong Liu,
Mee-Hyun Lee,
Ann M. Bode,
Zigang Dong

Affiliations

Seung Ho Shin: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Do Young Lim: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Kanamata Reddy: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Margarita Malakhova: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Fangfang Liu: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
Ting Wang: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
Mengqiu Song: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
Hanyong Chen: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Ki Beom Bae: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Joohyun Ryu: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Kangdong Liu: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
Mee-Hyun Lee: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
Ann M. Bode: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Zigang Dong: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA

DOI: https://doi.org/10.1016/j.ebiom.2017.09.029
Journal volume & issue: Vol. 25, no. C
pp. 22 – 31

Abstract

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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 formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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