Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells.
5-Fluorouracil (5-FU) is a cornerstone drug used in the treatment of colorectal cancer (CRC). However, the development of resistance to 5-FU and its analogs remain an unsolved problem in CRC treatment. In this study, we investigated the molecular mechanisms and tumor biological aspects of 5-FU resistance in CRC HCT116 cells. We established an acquired 5-FU-resistant cell line, HCT116RF10. HCT116RF10 cells were cross-resistant to the 5-FU analog, fluorodeoxyuridine. In contrast, HCT116RF10 cells were collaterally sensitive to SN-38 and CDDP compared with the parental HCT16 cells. Whole-exome sequencing revealed that a cluster of genes associated with the 5-FU metabolic pathway were not significantly mutated in HCT116 or HCT116RF10 cells. Interestingly, HCT116RF10 cells were regulated by the function of thymidylate synthase (TS), a 5-FU active metabolite 5-fluorodeoxyuridine monophosphate (FdUMP) inhibiting enzyme. Half of the TS was in an active form, whereas the other half was in an inactive form. This finding indicates that 5-FU-resistant cells exhibited increased TS expression, and the TS enzyme is used to trap FdUMP, resulting in resistance to 5-FU and its analogs.
['Kurasaka|Chinatsu|C|', 'Ogino|Yoko|Y|0000-0002-5349-2219', 'Sato|Akira|A|0000-0002-2239-6208']
D000964:Antimetabolites, Antineoplastic D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D019008:Drug Resistance, Neoplasm D005467:Floxuridine D005472:Fluorouracil D015972:Gene Expression Regulation, Neoplastic D045325:HCT116 Cells D006801:Humans D000077146:Irinotecan D017671:Platinum Compounds D013940:Thymidylate Synthase D000073359:Whole Exome Sequencing
5-Fluorouracil colorectal cancer cells thymidylate synthase drug resistance exome sequencing