Esculetin Inhibits Cancer Cell Glycolysis by Binding Tumor PGK2, GPD2, and GPI

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.

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“…To research reciprocal actions among these GRGs, we put the 326 GRGs into Cytoscape to create gene-gene interaction networks ( Figure 2B ). Cancer-associated proteins, such as GPI (glucose-6-phosphate isomerase), PKG1 (phosphoglycerate kinase 1) and HK (hexokinase), were identified to be major hubs in the resulting networks, which had previously been reported for their association with tumorigenesis ( 39 – 41 ).…”

Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning

“…GPD2 encodes an enzyme localized in the inner mitochondrial membrane, which catalyzes the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate. The upregulation of this gene increased the glycolysis in different cancer types ( Lu et al., 2020 ; Mikeli et al., 2020 ; Wu et al., 2020 ).…”

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

“…The activity of PGI1 can be inhibited by small molecules, i.e., the glucose analog, 2-deoxy-D-glucose (2-DG) ( Figure 1 ) (Pusapati et al, 2016 ). The small molecule inhibitor, Esculetin can directly bind PGI and repress its activity, which triggers apoptosis and inhibits tumor growth (Wu S. T. et al, 2020 ).…”