Journal
EXPERIMENTAL AND MOLECULAR MEDICINE
Volume 50, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s12276-018-0128-8
Keywords
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Funding
- Ministry of Education, Science, and Technology of China [2013CB911600, NCET-13-0868]
- Jiangsu Provincial Natural Science Foundation [BK20141448, CJ20160051]
- Research Fund for the Doctoral Program of Higher Education of China (RFDP) [20133207110005]
- Priority Academic Program Development of Jiangsu Higher Education Institutions [20110101]
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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 beta-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.
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