Pharmacological inhibition of the canonical Wnt/β-catenin signaling pathway sensitizes 5-fluorouracil-resistant colorectal cancer cells

BACKGROUND: The activation of the Wnt/β-catenin pathway with chemoresistance in colorectal cancer has been hypothesized. However, the use of specific inhibitors for targeting this pathway has not been well explored. In the present study, we analyze the activation of this pathway and its role in the stemness phenotype acquisition to regulate chemoresistance using our long-term 5-fluorouracil (5-FU) - resistant model of colorectal cancer cells, known to present epithelial-mesenchymal transition and enhanced migration and invasion. METHODS AND RESULTS: Initially by bioinformatic analyses we demonstrate the association between 5-FU resistance genes with those of a stem cell-like phenotype in patients with colon cancer. In addition, 5-FU-resistant cells displayed stemness characteristics, with upregulation of key stem cell marker (ALDH1A1) using reverse transcription-quantitative polymerase chain reaction. Further, 5-FU-resistant cells exhibited high Wnt/β-catenin pathway activity. Interestingly, treatment with LF3, an inhibitor of this pathway, re-sensitized the 5-FU-resistant cells, decreasing their proliferation. CONCLUSION: Wnt/β-catenin pathway activation plays a role in regulating key cellular events involved in chemoresistance. The study findings suggest the use of combinatorial therapies using conventional agents, such as 5-FU, and inhibitors of this pathway, as a useful therapeutic strategy to treat patients with colorectal cancer.