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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 resis...

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Autores principales: Kurasaka, Chinatsu, Ogino, Yoko, Sato, Akira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002131/
https://www.ncbi.nlm.nih.gov/pubmed/33805673
http://dx.doi.org/10.3390/ijms22062916
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author Kurasaka, Chinatsu
Ogino, Yoko
Sato, Akira
author_facet Kurasaka, Chinatsu
Ogino, Yoko
Sato, Akira
author_sort Kurasaka, Chinatsu
collection PubMed
description 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, HCT116R(F10). HCT116R(F10) cells were cross-resistant to the 5-FU analog, fluorodeoxyuridine. In contrast, HCT116R(F10) 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 HCT116R(F10) cells. Interestingly, HCT116R(F10) 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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spelling pubmed-80021312021-03-28 Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells Kurasaka, Chinatsu Ogino, Yoko Sato, Akira Int J Mol Sci Article 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, HCT116R(F10). HCT116R(F10) cells were cross-resistant to the 5-FU analog, fluorodeoxyuridine. In contrast, HCT116R(F10) 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 HCT116R(F10) cells. Interestingly, HCT116R(F10) 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. MDPI 2021-03-13 /pmc/articles/PMC8002131/ /pubmed/33805673 http://dx.doi.org/10.3390/ijms22062916 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kurasaka, Chinatsu
Ogino, Yoko
Sato, Akira
Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title_full Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title_fullStr Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title_full_unstemmed Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title_short Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells
title_sort molecular mechanisms and tumor biological aspects of 5-fluorouracil resistance in hct116 human colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002131/
https://www.ncbi.nlm.nih.gov/pubmed/33805673
http://dx.doi.org/10.3390/ijms22062916
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