Abstract
Glycolysis can improve the tolerance of tissue cells to hypoxia, and its intermediates provide raw materials for the synthesis and metabolism of the tumor cells. If it can inhibit the activity of glycolysis-related enzymes and control the energy metabolism of tumor, it can be targeted for the treatment of malignant tumor. The target proteins phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2), and glucose-6-phosphate isomerase (GPI) were screened by combining transcriptome, proteomics, and reverse docking. We detected the binding constant of the active compound using microscale thermophoresis (MST). It was found that esculetin bound well with three potential target proteins. Esculetin significantly inhibited the rate of glycolysis, manifested by differences of cellular lactate production and glucose consumption in HepG2 cells with or without esculetin. It was found that GPD2 bound strongly to GPI, revealing the direct interaction between the two glycolysis-related proteins. Animal tests have further demonstrated that esculetin may have anticancer effects by affecting the activity of PGK2, GPD2, and GPI. The results of this study demonstrated that esculetin can affect the glucose metabolism by binding to glycolytic proteins, thus playing an anti-tumor role, and these proteins which have direct interactions are potential novel targets for tumor treatment by esculetin.
Highlights
Through the analysis of liver cancer tissues, researchers found many characteristic metabolic markers, revealing the Warburg effect in liver cancer (Huang et al, 2013), that is, the abnormal metabolism of tumors was mainly manifested by the increase of glycolysis level, the inhibition of Tricarboxylic acid (TCA) cycle, and the significant down-regulation of dehydrogenase activity related to gluconeogenesis and fatty acid metabolism (Bensaad and Harris, 2014)
In vitro and in vivo experiments, these results demonstrate that esculetin could play an anti-tumor role by inhibiting the activity of glycolysis-related enzymes, among which GPD2 and glucose-6-phosphate isomerase (GPI) have a strong binding
The gene ontology (GO) analysis showed that the differential expression genes (DEGs) were significantly enriched in glucose 6-phosphate metabolic processes, acetyl-CoA biosynthesis, and glycosyl compound metabolic processes
Summary
Through the analysis of liver cancer tissues, researchers found many characteristic metabolic markers, revealing the Warburg effect in liver cancer (Huang et al, 2013), that is, the abnormal metabolism of tumors was mainly manifested by the increase of glycolysis level, the inhibition of Tricarboxylic acid (TCA) cycle, and the significant down-regulation of dehydrogenase activity related to gluconeogenesis and fatty acid metabolism (Bensaad and Harris, 2014). The exosomes of cancer cells promote the initiation of gluconeogenesis and detoxification of tumor-related fibroblasts, converting the metabolites of cancer cells, such as lactate and ammonia, into acetic acid and amino acids for cell proliferation (Spinelli et al, 2017; Dasgupta et al, 2018; Yan et al, 2018). Many experiments show that the PGK2, GPD2), and GPI are key enzymes of glycolysis, and in promoting tumor cells play an important role in the process of glycolysis. These enzymes may be potential biomarkers and target tumor diagnosis and treatment
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