IADR Abstract Archives
2-deoxy-D-glucose and Dichloroacetate Affect the Glucose Metabolic System of OSCC
Objectives: Cancer cells are reported to obtain energy efficiently through the enhancement of glycolysis (Warburg effect), suggesting that inhibition of glycolysis may suppress cancer cells. Our previous study has shown that the glucose metabolic activity of oral squamous cell carcinoma (OSCC) cells was decreased by 2-deoxy-D-glucose (2DG) and dichloroacetate (DCA). However, the inhibitory mechanism of 2DG and DCA are still unknown. Therefore, this study aimed to clarify the mechanism through metabolomic approach.
Methods: HSC-3 (OSCC cell line) was used. According to our previous study, the cultured cells were mixed with 5 mM glucose and 5 mM DCA, 2 mM 2DG or saline (control), and the metabolic activity was monitored for 20 min at 37°C and pH 7.5 using pH-stat system. At 0 and 20 min, the cells were collected, and metabolites in the cells were extracted and pretreated for metabolome analysis. The levels of metabolic intermediates in glycolysis, TCA cycle and pentose-phosphate-pathway (PPP) were measured with capillary electrophoresis and time-of-flight mass spectrometer.
Results: 2DG decreased the level of pyruvate and 3-phosphoglycerate in glycolysis, 6-phosphogluconate in PPP, and malate, succinate, citrate in TCA cycle by 37.9-62.3 %. DCA decreased the level of pyruvate and 3-phosophoglycerate in glycolysis, 6-phosphogluconate, ribose 5-phosphate and ribulose 5-phosohate in PPP by 37.0-100 %, while metabolite levels in TCA cycle were increased or not changed.
Conclusions: Our results indicate that 2DG inhibited the whole metabolic activity, while DCA inhibited glycolysis and PPP, but not TCA cycle. These observations suggest that DCA can switch the glucose metabolic pathway from anaerobic glycolysis (lactate production) to TCA cycle. DCA is reported to activate pyruvate dehydrogenase (PDH), an enzyme responsible to link pyruvate to TCA cycle, through the inhibition of PDH kinase, an enzyme that inactivates PDH. DCA might function in this way even within a short period.
Methods: HSC-3 (OSCC cell line) was used. According to our previous study, the cultured cells were mixed with 5 mM glucose and 5 mM DCA, 2 mM 2DG or saline (control), and the metabolic activity was monitored for 20 min at 37°C and pH 7.5 using pH-stat system. At 0 and 20 min, the cells were collected, and metabolites in the cells were extracted and pretreated for metabolome analysis. The levels of metabolic intermediates in glycolysis, TCA cycle and pentose-phosphate-pathway (PPP) were measured with capillary electrophoresis and time-of-flight mass spectrometer.
Results: 2DG decreased the level of pyruvate and 3-phosphoglycerate in glycolysis, 6-phosphogluconate in PPP, and malate, succinate, citrate in TCA cycle by 37.9-62.3 %. DCA decreased the level of pyruvate and 3-phosophoglycerate in glycolysis, 6-phosphogluconate, ribose 5-phosphate and ribulose 5-phosohate in PPP by 37.0-100 %, while metabolite levels in TCA cycle were increased or not changed.
Conclusions: Our results indicate that 2DG inhibited the whole metabolic activity, while DCA inhibited glycolysis and PPP, but not TCA cycle. These observations suggest that DCA can switch the glucose metabolic pathway from anaerobic glycolysis (lactate production) to TCA cycle. DCA is reported to activate pyruvate dehydrogenase (PDH), an enzyme responsible to link pyruvate to TCA cycle, through the inhibition of PDH kinase, an enzyme that inactivates PDH. DCA might function in this way even within a short period.