Yu Junhui, Yang Kui, Zheng Jianbao, Zhao Wei, Sun Xuejun
Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, 710061, Xi'an, China.
Cancer Gene Ther. 2021 Jun;28(6):590-601. doi: 10.1038/s41417-020-00239-8. Epub 2020 Oct 13.
The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.
法尼酯X受体（FXR）在结直肠癌发生中的肿瘤抑制作用支持恢复FXR表达作为一种新的治疗策略。然而，复杂的信号网络和肿瘤异质性阻碍了FXR激动剂在临床环境中的有效性。这些困难凸显了识别具有效力和特异性的药物组合以增强FXR激动剂抗肿瘤作用的重要性。在本研究中，我们发现β-连环蛋白水平影响FXR激动剂奥贝胆酸（OCA）对结肠癌细胞的抗肿瘤作用。机制研究在结肠癌细胞中鉴定出一种新的FXR/β-连环蛋白复合物。此外，β-连环蛋白的缺失加速了FXR的核定位并增强了其对小异二聚体伴侣（SHP）启动子的占据，从而使结肠癌细胞对OCA敏感。此外，我们利用药物组合研究发现，抗寄生虫药物硝唑尼特（NTZ）可消除β-连环蛋白表达，并在结肠癌细胞中与OCA协同作用。OCA加NTZ的组合通过协同上调SHP表达在体外和体内对结直肠癌发挥协同肿瘤抑制作用。总之，我们的研究为FXR激动剂与β-连环蛋白抑制剂联合用于对抗结直肠癌的临床应用提供了有用的证据。
