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

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

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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.

Original language	English (US)
Pages (from-to)	22-31
Number of pages	10
Journal	EBioMedicine
Volume	25
DOIs	https://doi.org/10.1016/j.ebiom.2017.09.029
State	Published - Nov 2017

Bibliographical note

Funding Information:
The research was supported by The Hormel Foundation and National Institutes of Health ( R01-CA187027 ). S.H.S. was supported by a Bioinformatics and Computational Biology fellowship and a Doctoral Dissertation Fellowship from the University of Minnesota.

Publisher Copyright:
© 2017 The Authors

Keywords

Colorectal cancer
HI-B1
Patient-derived xenograft
Precision medicine
Small molecule inhibitor
β-catenin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2017.09.029

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

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",

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

note = "Funding Information: The research was supported by The Hormel Foundation and National Institutes of Health ( R01-CA187027 ). S.H.S. was supported by a Bioinformatics and Computational Biology fellowship and a Doctoral Dissertation Fellowship from the University of Minnesota. Publisher Copyright: {\textcopyright} 2017 The Authors",

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doi = "10.1016/j.ebiom.2017.09.029",

language = "English (US)",

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AU - Shin, Seung Ho

AU - Lim, Do Young

AU - Reddy, Kanamata

AU - Malakhova, Margarita

AU - Liu, Fangfang

AU - Wang, Ting

AU - Song, Mengqiu

AU - Chen, Hanyong

AU - Bae, Ki Beom

AU - Ryu, Joohyun

AU - Liu, Kangdong

AU - Lee, Mee Hyun

AU - Bode, Ann M.

AU - Dong, Zigang

N1 - Funding Information: The research was supported by The Hormel Foundation and National Institutes of Health ( R01-CA187027 ). S.H.S. was supported by a Bioinformatics and Computational Biology fellowship and a Doctoral Dissertation Fellowship from the University of Minnesota. Publisher Copyright: © 2017 The Authors

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

KW - Colorectal cancer

KW - HI-B1

KW - Patient-derived xenograft

KW - Precision medicine

KW - Small molecule inhibitor

KW - β-catenin

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

Abstract

Bibliographical note

Keywords

UN SDGs

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