Relationship between anticancer sensitivities and cellular respiration properties in 5-fluorouracil-resistant HCT116 human colorectal cancer cells

Abstract

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, HCT116R^F10 , and examined its biological features and 5-FU resistance mechanisms. In this study, we evaluated the 5-FU sensitivity and cellular respiration dependency of HCT116R^F10 cells and parental HCT116 cells under conditions of high- and low-glucose concentrations. Both HCT116R^F10 and parental HCT116 cells were more sensitive to 5-FU under low-glucose conditions compared with high-glucose conditions. Interestingly, HCT116R^F10 and parental HCT116 cells exhibited altered cellular respiration dependence for glycolysis and mitochondrial respiration under high- and low-glucose conditions. Additionally, HCT116R^F10 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 HCT116R^F10 cells compared with HCT116 cells. The ATP production rates in HCT116R^F10 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.

Keywords: 5-fluorouracil; HCT116; cellular respiration; colorectal cancer cell; drug resistance; glucose restriction.