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

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

来源：EBioMedicine, 2017, 25: 22-31.

DOI：10.1016/j.ebiom.2017.09.029

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

Colorectal cancer is associated with aberrant activation of the Wnt pathway. beta-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 beta-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on beta-catenin. The formation of the beta-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with beta-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of beta-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of beta-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the beta-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer.

• 出版日期2017-11
• 单位郑州大学