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

45 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.",

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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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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

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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.

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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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