The major metabolite
of the anticancer agent 5-fluorouracil (5-FU)
is 5-fluorodeoxyuridine monophosphate (FdUMP), which is a potent inhibitor
of thymidylate synthase (TS). Recently, we hypothesized that 5-FU-resistant
colorectal cancer (CRC) cells have increased levels of TS protein
relative to 5-FU-sensitive CRC cells and use a fraction of their TS
to trap FdUMP, which results in resistance to 5-FU. In this study,
we analyzed the difference between the regulation of the balance of
the free, active form of TS and the inactive FdUMP-TS form in 5-FU-resistant
HCT116 cells and parental HCT116 cells. Silencing of TYMS, the gene that encodes TS, resulted in greater enhancement of the
anticancer effect of 5-FU in the 5-FU-resistant HCT116RF10 cells than in the parental HCT116 cells. In addition, the trapping
of FdUMP by TS was more effective in the 5-FU-resistant HCT116RF10 cells than in the parental HCT116 cells. Our observations
suggest that the regulation of the balance between the storage of
the active TS form and the accumulation of FdUMP-TS is responsible
for direct resistance to 5-FU. The findings provide a better understanding
of 5-FU resistance mechanisms and may enable the development of anticancer
strategies that reverse the sensitivity of 5-FU resistance in CRC
cells.
The properties of 5-fluorouracil (5-FU), including its chemical synthesis and widespread anticancer effects, in fundamental and clinical terms were first published in 1957. 1-3 5-FU is still widely used today, mainly for the treatment of gastrointestinal cancers, such as colorectal cancer (CRC). 4,5 5-FU is converted to the active metabolite 5-fluorodeoxyuridine monophosphate (FdUMP), which is a potent inhibitor of thymidylate synthase (TS). 3,[5][6][7][8] FdUMP forms a ternary complex with TS and 5, 10-methylenetetrahydrofolate (5, 10-CH 2 -THF). 4-9 TS catalyzes the conversion of dUMP to dTMP using the coenzyme 5, 10-CH 2 -THF as a methyl donor. 10 The ternary complex inhibits TS function, depletes intracellular dTTP, dNTP pools, and subsequently inhibits DNA synthesis. [3][4][5]8
5‐Fluorouracil (5‐FU) is widely used for colorectal cancer (CRC) treatment; however, continuous treatment of CRC cells with 5‐FU can result in acquired resistance, and the underlying mechanism of 5‐FU resistance remains unclear. We previously established an acquired 5‐FU‐resistant CRC cell line, HCT116RF10, and examined its biological features and 5‐FU resistance mechanisms. In this study, we evaluated the 5‐FU sensitivity and cellular respiration dependency of HCT116RF10 cells and parental HCT116 cells under conditions of high‐ and low‐glucose concentrations. Both HCT116RF10 and parental HCT116 cells were more sensitive to 5‐FU under low‐glucose conditions compared with high‐glucose conditions. Interestingly, HCT116RF10 and parental HCT116 cells exhibited altered cellular respiration dependence for glycolysis and mitochondrial respiration under high‐ and low‐glucose conditions. Additionally, HCT116RF10 cells showed a markedly decreased ATP production rate compared with HCT116 cells under both high‐ and low‐glucose conditions. Importantly, glucose restriction significantly reduced the ATP production rate for both glycolysis and mitochondrial respiration in HCT116RF10 cells compared with HCT116 cells. The ATP production rates in HCT116RF10 and HCT116 cells were reduced by approximately 64% and 23%, respectively, under glucose restriction, suggesting that glucose restriction may be effective at enhancing 5‐FU chemotherapy. Overall, these findings shed light on 5‐FU resistance mechanisms, which may lead to improvements in anticancer treatment strategies.
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