Wnt pathway is involved in 5-FU drug resistance of colorectal cancer cells

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. 5-Fluorouracil (5-FU) is widely used in the treatment of cancers, but its antineoplastic activity is limited in drug-resistant cancer cells. To investigate the detailed mechanism of 5-FU resistance, we developed a model of 5-FU-resistant cells from HCT-8 cells, a well-established colorectal cancer cell line. We found that the drug-resistant cells demonstrated high expression of TCF4 and β-catenin, indicating an upregulated Wnt pathway. A microarray analysis revealed that the suppression of the checkpoint kinase 1 (CHK1) pathway explained the resistance to 5-FU, especially in p53 wild-type cancer cells such as HCT-8. Our data also demonstrated that the CHK1 pathway is suppressed by the Wnt pathway in 5-FU-resistant cells. In summary, we have discovered a novel mechanism for 5-FU resistance mediated by histone deacetylation, which also revealed the crosstalk between the Wnt pathway and CHK1 pathway. The interaction between two signaling pathways may be related to resistance to a leading cancer drug in colorectal cancer cells. The drug 5-fluorouracil (5-FU) is widely used to limit malignant cell proliferation, but some cancers, including colorectal cancers, are resistant to 5-FU. Zhigang Guo at Nanjing Normal University, China, and co-workers have uncovered the signaling pathways behind 5-FU resistance in colorectal cancer cell lines. They found that 5-FU-resistant cells expressed high levels of two proteins indicative of an over-active Wnt signaling pathway, a crucial pathway in healthy development, the disruption of which is implicated in many diseases. This upregulated pathway suppressed another signaling pathway, leading to reduced cancer cell death. This interaction between the pathways could prove to be a valuable therapeutic target to limit resistance to 5-FU.