Abstract
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.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer-related death [1]
The complicated signaling network and tumor heterogeneity might hinder the effectiveness of Farnesoid X receptor (FXR) agonists in cancer treatment [22]
The results showed that RKO and HCT116 cells showed the most sensitivity to Obeticholic acid (OCA) with IC50 values of 0.9211 and 0.8377 μM, respectively, whereas DLD-1 and HT-29 cells were moderately resistant to OCA with IC50 values of 2.044 and 2.993 μM, respectively (Fig. 1a)
Summary
Colorectal cancer (CRC) is the second most common cause of cancer-related death [1]. Approximately 1,800,000 new cases are diagnosed as CRC every year. Due to distant metastasis and relapse, most advanced-stage of CRC has a poor prognosis [2, 3]. The five-year survival rate of stage I CRC patients exceeds 90%; the fiveyear survival rate of stage IV CRC patients is slightly higher than 10% [4]. An increasing number of genetic and molecular alterations have been recognized in colorectal. These authors contributed : Junhui Yu, Kui Yang
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