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

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

EBioMedicine. 2017 Nov:25:22-31. doi: 10.1016/j.ebiom.2017.09.029. Epub 2017 Sep 27.

Authors

Affiliations

¹ The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; Program in Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455, USA.
² The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
³ The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
⁴ The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
⁵ The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China; The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.
⁶ The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; Program in Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455, USA; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China; The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China. Electronic address: zgdong@hi.umn.edu.

Abstract

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.

Keywords: Colorectal cancer; HI-B1; Patient-derived xenograft; Precision medicine; Small molecule inhibitor; β-catenin.

MeSH terms

Animals
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Gene Expression Regulation, Neoplastic / drug effects
Humans
Mice
Multiprotein Complexes / drug effects
Multiprotein Complexes / genetics
Small Molecule Libraries / administration & dosage*
Small Molecule Libraries / chemical synthesis
Transcription Factor 4 / antagonists & inhibitors
Transcription Factor 4 / genetics*
Wnt Signaling Pathway / drug effects
Xenograft Model Antitumor Assays
beta Catenin / antagonists & inhibitors
beta Catenin / genetics*

Substances

CTNNB1 protein, human
Multiprotein Complexes
Small Molecule Libraries
TCF4 protein, human
Transcription Factor 4
beta Catenin

Grants and funding

R01 CA187027/CA/NCI NIH HHS/United States