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Fig. 1 | Cancer & Metabolism

Fig. 1

From: Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

Fig. 1

Metabolomic profiling of enolase-inhibitor treated glioma cell lines indicates a profound disruption in anaplerosis, which correlates with the sensitivity. a–c Sensitivity of glioma cells to the enolase inhibitor is reflected by their ENO1 status. a Dose-response curves of ENO1 homozygously deleted (D423; red, N=4), ENO1-heterozygously deleted (D502; green, N=4; U343; orange, N=4), and ENO1 wild type (LN319; grey N=4) cells treated with the enolase inhibitor POMHEX at the indicated doses. Error bars represent the standard error of mean. b After 5 days of treatment, the cells were fixed in 10% formalin and stained with crystal violet dye to measure the terminal cell density. The terminal cell density is expressed relative to the untreated controls. c A representative table with the IC50 values of POMHEX across different cell lines strongly indicates that ENO1 homozygously deleted cells are selectively sensitive, while ENO1 heterozygotes display intermediate sensitivity to POMHEX. d-e Enolase inhibitor causes a profound disruption in the TCA cycle. Cells were treated with varying concentrations of POMHEX in DMEM media and the metabolites were extracted in 80% cold methanol after 72 h of drug treatment. The extracted metabolites were subjected to metabolomic analysis by mass-spectroscopy. d Schematic showing the glycolytic and TCA cycle metabolites that are altered by POMHEX treatment. Red arrows indicate metabolites that are elevated, while blue arrows indicate metabolites that are decreased in response to POMHEX. e Lactate levels are shown as an indicator of glycolysis inhibition in response to the enolase inhibitor POMHEX. Two TCA cycle intermediates citrate and malate are shown as representative metabolites in the TCA cycle that are altered in a dose dependent manner as a result of enolase inhibition. The effects of enolase inhibition on TCA cycle metabolites correlate with the levels of ENO1 in different cell lines, with the ENO1-homozygously deleted cells exhibiting the most profound change, followed by ENO1 heterozygous cells showing intermediate effect while ENO1 intact wild type cells sustaining no significant effect (see Supplemental figure S1 and S2 for a full panel of glycolytic and TCA cycle metabolites)

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