Esculetin inhibits cancer cell glycolysis by binding tumor PGK2, GPD2, and GPI
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ABSTRACT:
PROVIDER: PRJNA599568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10849372.fastq.gz | Fastqsanger.gz | |||
| SRR10849373.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-03-03 | PXD017819 | Pride
Project description:The target proteins phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2)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.
2020-01-09 | GSE143274 | GEO
Project description: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.
| S-EPMC7118906 | biostudies-literature
Project description:Postprandial dyslipidemia is a recognized risk factor for atherosclerosis. High-density lipoprotein (HDL)-mediated reverse cholesterol transport plays a crucial role in mitigating this risk by clearing postprandial lipids. This study aimed to investigate the impact of esculetin, a 4-Hydroxycoumarin, on postprandial cholesterol metabolism and excretion after a high-fat meal. Esculetin significantly elevated postprandial HDL cholesterol levels in serum and postprandial bile acid levels in bile, and altered serum metabolomics in mice fed a high-fat meal, indicating esculetin promotes HDL-driven cholesterol excretion after a high-fat meal. Furthermore, esculetin administration in mice led to an increase in the ratio and phagocytic activity of a subset of adipose tissue macrophages (ATMs) expressing high levels of CD36 and Tim4. Inhibition of CD36 by Sulfo-N-succinimidyl oleate (SSO) blocked esculetin-induced elevation of postprandial serum HDL and bile acid levels in bile. Additionally, esculetin demonstrated the ability to increase the uptake of oxidized LDL (ox-LDL) via CD36 in a macrophage cell line, which might involve alteration of the epigenetic landscape controlled by CCAAT enhancer-binding protein beta (C/EBPβ). Esculetin-induced increased uptake of ox-LDL and elevation of CD36 was inhibited in C/EBPβ-deficient cells. A relatively higher expression of C/EBPβ was observed in CD36+ ATMs, and esculetin increased the ratio of C/EBPβ+ CD36+ ATMs in mice fed a lipid-rich meal. Overall, these findings suggest esculetin promotes HDL-mediated postprandial cholesterol excretion by directly binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
2025-04-21 | GSE248616 | GEO
Project description:Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase (MMP) activity through 1:1 stochiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1-GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells (RCC) show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify potential mechanisms driving these effects. Significant changes in inhibitor of DNA binding (IDs), TGF-β1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-β1 signaling mediated by inhibition of proteolytic processing of latent TGF-β1 by TIMP-1-GPI. Activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells (RCC) show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify potential mechanisms driving these effects. Significant changes in inhibitor of DNA binding (IDs), TGF-β1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-β1 signaling mediated by inhibition of proteolytic processing of latent TGF-β1 by TIMP-1-GPI.
2012-08-23 | GSE40301 | GEO
Project description:Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase (MMP) activity through 1:1 stochiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1-GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells (RCC) show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify potential mechanisms driving these effects. Significant changes in inhibitor of DNA binding (IDs), TGF-β1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-β1 signaling mediated by inhibition of proteolytic processing of latent TGF-β1 by TIMP-1-GPI. Activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells (RCC) show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify potential mechanisms driving these effects. Significant changes in inhibitor of DNA binding (IDs), TGF-β1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-β1 signaling mediated by inhibition of proteolytic processing of latent TGF-β1 by TIMP-1-GPI. Renal cell carcinoma cells were transfected with empty vector, rhTimp1 and 2 concentrations of Timp1-GPI fusion protein
2012-08-23 | E-GEOD-40301 | biostudies-arrayexpress
Project description:Postprandial dyslipidemia is a recognized risk factor for atherosclerosis. High-density lipoprotein (HDL)-mediated reverse cholesterol transport plays a crucial role in mitigating this risk by clearing postprandial lipids. This study aimed to investigate the impact of esculetin, a 4-Hydroxycoumarin, on postprandial cholesterol metabolism and excretion after a high-fat meal. Esculetin significantly elevated postprandial HDL cholesterol levels in serum and postprandial bile acid levels in bile, and altered serum metabolomics in mice fed a high-fat meal, indicating esculetin promotes HDL-driven cholesterol excretion after a high-fat meal. Furthermore, esculetin administration in mice led to an increase in the ratio and phagocytic activity of a subset of adipose tissue macrophages (ATMs) expressing high levels of CD36 and Tim4. Inhibition of CD36 by Sulfo-N-succinimidyl oleate (SSO) blocked esculetin-induced elevation of postprandial serum HDL and bile acid levels in bile. Additionally, esculetin demonstrated the ability to increase the uptake of oxidized LDL (ox-LDL) via CD36 in a macrophage cell line, which might involve alteration of the epigenetic landscape controlled by CCAAT enhancer-binding protein beta (C/EBPβ). Esculetin-induced increased uptake of ox-LDL and elevation of CD36 was inhibited in C/EBPβ-deficient cells. A relatively higher expression of C/EBPβ was observed in CD36+ ATMs, and esculetin increased the ratio of C/EBPβ+ CD36+ ATMs in mice fed a lipid-rich meal. Moreover, the direct interaction between esculetin and C/EBPβ were observed by Terahertz chemical microscope. Overall, these findings suggest esculetin promotes HDL-mediated postprandial cholesterol excretion by directly binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
2024-06-12 | GSE234771 | GEO
Project description:Postprandial dyslipidemia is a significant risk factor for atherosclerotic cardiovascular diseases. High-density lipoprotein (HDL)-driven reverse cholesterol transport (RCT) plays a crucial role in clearing postprandial lipids. In this study, we aimed to investigate the role of esculetin, a hypolipidemic substance, in regulating postprandial cholesterol metabolism. We measured postprandial cholesterol levels and conducted metabolomics and transcriptomics studies to understand the effect and underlying mechanism of esculetin on postprandial cholesterol metabolism in mice fed a lipid-rich meal. We found that esculetin significantly elevated the postprandial HDL cholesterol levels and induced alterations in postprandial serum metabolomics and hepatic transcriptomics which involved in the key steps of HDL-driven RCT including lipid metabolism, ABC transporters and bile acid biosynthesis and secretion. Additionally, the ratio and the phagocytic activity of an adipose tissue macrophage subset highly expressing CD36 and Tim4 increased following esculetin administration in mice. CCAAT enhancer-binding protein beta (C/EBPβ), a key transcription factor, was involved in the effect of esculetin on macrophages phagocytosis in ox-LDL-stimulated macrophages cells. Therefore, esculetin appears to elevate postprandial HDL levels and regulate postprandial cholesterol metabolism which are associated with the increased phagocytosis of adipose tissue macrophages and C/EBPβ.
2025-04-21 | GSE276565 | GEO
Project description:Rationale: Exogenous lipid metabolism, influenced by dietary intake, contributes to postprandial dyslipidemia. Adipose tissue macrophages (ATMs) mediate the phagocytosis of postprandial lipids from the exogenous diet, generating high-density lipoprotein (HDL) particles that facilitate lipid circulation and excretion. However, the underlying mechanisms remain poorly understood. This study investigates the effects of esculetin, a coumarin compound, on postprandial cholesterol circulation and excretion following a high-fat meal. Methods: Mice were fed a lipid-rich meal for three days to assess the effects of esculetin on postprandial lipid circulation, using serum lipid profiling and metabolomics analysis. Epididymal white adipose tissue (eWAT) removal and flow cytometry were performed to analyze ATMs and confirm their role in mediating esculetin’s effects on postprandial lipemia. Epigenetic profiling, transcriptome analysis, chromatin immunoprecipitation, and Terahertz chemical microscopy were employed to elucidate the molecular targets and mechanisms of esculetin. Results: Esculetin significantly elevates postprandial HDL cholesterol levels to values comparable to pitavastatin and modifies serum metabolites involved in bile-mediated cholesterol excretion, leading to increased bile acid concentrations in the bile. This effect is mediated by an increased ratio and phagocytic activity of a subset of ATMs expressing the scavenger receptor CD36, as eWAT removal and CD36 blockade inhibit this response. Furthermore, esculetin enhances the uptake of oxidized LDL via CD36, as demonstrated in cultured macrophages, and induces epigenetic changes controlled by the key transcription factor C/EBPβ, accompanied by increased C/EBPβ binding to the Cd36 promoter. A direct interaction between esculetin and C/EBPβ was observed using Terahertz chemical microscopy. Additionally, the activation of C/EBPβ by esculetin in ATMs was confirmed in vivo. Conclusion: Esculetin accelerates postprandial lipid circulation by binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
2025-04-21 | GSE292378 | GEO
Project description: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 the pathway comprising these proteins which have direct interactions are a potential novel targets for tumor treatment by esculetin.
2020-01-20 | PXD017062 | Pride