Abstract
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.
Highlights
Considerable progress has been made in the treatment of colorectal cancer (CRC) in recent years, it remains as one of the leading causes of cancer-related death worldwide[1]
Establishment of 5-FU-resistant CRC cells To obtain 5-FU-resistant cells, parental HCT-8 colorectal cells were treated with increasing concentrations of 5-FU
When drug resistance is elevated in HCT-8R, an elevation in base excision repair (BER) activity should be observed
Summary
Considerable progress has been made in the treatment of colorectal cancer (CRC) in recent years, it remains as one of the leading causes of cancer-related death worldwide[1]. 5-Fluorouracil (5-FU) remains a commonly used chemotherapeutic drug in cancer treatments and clinical studies[2]. An increased understanding of the 5-FU mechanism has promoted the progress of new strategies that increase antineoplastic activity. The antineoplastic efficacy of 5-FU is attributed to its ability to increase DNA damage, which results in cell growth arrest and apoptosis. Clinical efficacy is reduced due to the chemotherapeutic drug resistance of cancer cells. Despite extensive research in recent years, drug resistance remains a critical limitation to the clinical application of 5-FU and related
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