Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
1
Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
2
Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Valentina De Falco
Int. J. Mol. Sci. 2021, 22(6), 2916; https://doi.org/10.3390/ijms22062916
Received: 1 February 2021 / Revised: 26 February 2021 / Accepted: 10 March 2021 / Published: 13 March 2021
(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)
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.
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Keywords:
colorectal cancer cells; drug resistance; 5-Fluorouracil; thymidylate synthase; exome sequencing
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MDPI and ACS Style
Kurasaka, C.; Ogino, Y.; Sato, A. Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells. Int. J. Mol. Sci. 2021, 22, 2916. https://doi.org/10.3390/ijms22062916
AMA Style
Kurasaka C, Ogino Y, Sato A. Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells. International Journal of Molecular Sciences. 2021; 22(6):2916. https://doi.org/10.3390/ijms22062916
Chicago/Turabian StyleKurasaka, Chinatsu; Ogino, Yoko; Sato, Akira. 2021. "Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells" Int. J. Mol. Sci. 22, no. 6: 2916. https://doi.org/10.3390/ijms22062916
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