Regulation of 5-fluorodeoxyuridine Monophosphate-thymidylate Synthase Ternary Complex Levels by Autophagy Confers Resistance to 5-fluorouracil

Overview

Journal FASEB Bioadv

Specialty Biology

Date 2023 Jan 16

PMID 36643896

Authors

Nana Nishizawa

Chinatsu Kurasaka

Yoko Ogino

Akira Sato

Affiliations

Soon will be listed here.

Abstract

5-Fluorouracil (5-FU) is a cornerstone drug used to treat colorectal cancer (CRC). However, the prolonged exposure of CRC cells to 5-FU results in acquired resistance. We have previously demonstrated that levels of the 5-fluorodeoxyuridylate (FdUMP) covalent complex with thymidylate synthase (FdUMP-TS) and free-TS (native enzyme) are higher in 5-FU-resistant CRC cells than in the parental cell line (HCT116). Accordingly, resistant cells may have an efficient system for trapping and removing FdUMP-TS, thus imparting resistance. In this study, using a model of 5-FU-resistant CRC cells generated by repeated exposure, the role of autophagy in the elimination of FdUMP-TS in resistant cells was investigated. The resistant cells showed greater sensitivity to autophagy inhibitors than that of parental cells. Autophagy inhibition increased 5-FU cytotoxicity more substantially in resistant cells than in parental cells. Furthermore, autophagy inhibition increased FdUMP-TS protein accumulation in resistant cells. Our findings suggest that resistance to 5-FU is mediated by autophagy as a system to eliminate FdUMP-TS and may guide the use and optimization of combination therapies involving autophagy inhibitors.

Citing Articles

Regulation of 5-fluorodeoxyuridine monophosphate-thymidylate synthase ternary complex levels by autophagy confers resistance to 5-fluorouracil.

Nishizawa N, Kurasaka C, Ogino Y, Sato A FASEB Bioadv. 2023; 5(1):43-51.

PMID: 36643896 PMC: 9832531. DOI: 10.1096/fba.2022-00099.

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