The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; Program in Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455, USA.
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
EBioMedicine. 2017 Nov;25:22-31. doi: 10.1016/j.ebiom.2017.09.029. Epub 2017 Sep 27.
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.
结直肠癌与 Wnt 通路的异常激活有关。β-连环蛋白通过与 T 细胞因子 4（TCF4）相互作用转录癌基因，在 Wnt 通路中发挥重要作用。我们合成了一种小分子，称为 HI-B1，并评估了该化合物诱导的信号变化和生物学后果。HI-B1 抑制β-连环蛋白/TCF4 荧光素酶活性，并优先导致依赖β-连环蛋白生存的癌细胞凋亡。HI-B1 通过与β-连环蛋白的直接相互作用破坏β-连环蛋白/TCF4 复合物的形成。结直肠癌患者来源的异种移植（PDX）研究表明，与β-连环蛋白表达水平较低的肿瘤相比，β-连环蛋白表达水平较高的肿瘤对 HI-B1 治疗更为敏感。PDX 肿瘤对 HI-B1 的不同敏感性取决于β-连环蛋白的表达水平，并且可能进一步用于开发生物标志物和针对结肠癌的治疗应用。
