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Nature Communications Jan 2020Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development....
Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.
Topics: Acetylglucosamine; Amino Acid Motifs; Animals; Cell Line, Tumor; Citric Acid Cycle; Colonic Neoplasms; Glycolysis; Humans; Male; Mice; Mice, Nude; Mitochondria; Phosphoglycerate Kinase; Pyruvate Dehydrogenase Complex
PubMed: 31911580
DOI: 10.1038/s41467-019-13601-8 -
Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.International Journal of Molecular... Sep 2022Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically... (Review)
Review
Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
Topics: Glycolysis; Hexokinase; Humans; Neoplasms; Phosphofructokinase-1; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Pyruvates; Tumor Microenvironment
PubMed: 36077431
DOI: 10.3390/ijms231710037 -
Journal of Translational Medicine Feb 2022Long noncoding RNA NEAT1 has been implicated in glioma progression. However, the effect of NEAT1 on glycolysis of glioma cell and the potential mechanism remain unclear.
BACKGROUND
Long noncoding RNA NEAT1 has been implicated in glioma progression. However, the effect of NEAT1 on glycolysis of glioma cell and the potential mechanism remain unclear.
METHODS
In vitro experiments, including CCK-8, colony formation, ECAR, and lactate detection assays were performed to evaluate the effect of NEAT1 on proliferation and glycolysis of glioma cell. RNA pulldown and RIP assays were performed to identify the interaction between NEAT1 and PGK1. Truncated mutation of NEAT1 and PGK1 was used to confirm the specific interactive domains between NEAT1 and PGK1. Animal studies were performed to analyze the effect of NEAT1/PGK1 on glioma progression.
RESULTS
NEAT1 knockdown significantly suppressed the proliferation and glycolysis of glioma cells. NEAT1 could specifically interact with PGK1, which promotes PGK1 stability. Hairpin A of NEAT1 is essential for interaction with M1 domain of PGK1. Depletion of NEAT1 markedly inhibited tumor growth in mice, while PGK1 could reverse this effect. Higher expression of NEAT1 was associated with poor overall survival of GBM patients.
CONCLUSIONS
NEAT1 over expression promotes glioma progression through stabilizing PGK1. NEAT1/PGK1 axis is a candidate therapeutic target for glioma treatment.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Phosphoglycerate Kinase; RNA, Long Noncoding
PubMed: 35123484
DOI: 10.1186/s12967-022-03273-2 -
Nature Communications Feb 2023Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays...
Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal.
Topics: Humans; Liver; Oxidative Phosphorylation; Carcinogenesis; Lactic Acid; Mitochondria; RNA, Circular; RNA, Mitochondrial; Phosphoglycerate Kinase
PubMed: 36849569
DOI: 10.1038/s41467-023-36651-5 -
EBioMedicine Nov 2020Disordered folliculogenesis is a core characteristic of polycystic ovary syndrome (PCOS) and androgen receptors (ARs) are closely associated with hyperandrogenism and...
BACKGROUND
Disordered folliculogenesis is a core characteristic of polycystic ovary syndrome (PCOS) and androgen receptors (ARs) are closely associated with hyperandrogenism and abnormalities in folliculogenesis in PCOS. However, whether the new AR binding partner phosphoglycerate kinase 1 (PGK1) in granulosa cells (GCs) plays a key role in the pathogenesis of PCOS remains unclear.
METHODS
We identified the new AR binding partner PGK1 by co-IP (co-immunoprecipitation) in luteinized GCs, and reconfirmed by co-IP, co-localization and GST pull down assay, and checked PGK1 expression levels with qRT-PCR and western blotting. Pharmaceuticals rescue assays in mice, and metabolism assay, AR protein stability and RNA-seq of PGK1 targets in cells proved the function in PCOS.
FINDINGS
PGK1 and AR are highly expressed in PCOS luteinized GCs and PCOS-like mouse ovarian tissues. PGK1 regulated glucose metabolism and deteriorated PCOS-like mouse metabolic disorder, and paclitaxel rescued the phenotype of PCOS-like mice and reduced ovarian PGK1 and AR protein levels. PGK1 inhibited AR ubiquitination levels and increased AR stability in an E3 ligase SKP2-dependent manner. Additionally, PGK1 promoted AR nuclear translocation, and RNA-seq data showed that critical ovulation-related genes were regulated by the PGK1-AR axis.
INTERPRETATION
PGK1 regulated GCs metabolism and interacted with AR to regulate the expression of key ovulation genes, and also mediated cell proliferation and apoptosis, which resulted in the etiology of PCOS. This work highlights the pathogenic mechanism and represents a novel therapeutic target for PCOS.
FUNDING
National Key Research and Development Program of China; National Natural Science Foundation of China grant.
Topics: Adult; Animals; Apoptosis; Biomarkers; Carbohydrate Metabolism; Cell Line; Disease Models, Animal; Disease Susceptibility; Female; Gene Expression; Gene Expression Profiling; Glucose; Granulosa Cells; Humans; Immunohistochemistry; Metabolic Diseases; Mice; Models, Biological; Ovulation; Phosphoglycerate Kinase; Polycystic Ovary Syndrome; Protein Binding; Protein Stability; Protein Transport; Receptors, Androgen; S-Phase Kinase-Associated Proteins
PubMed: 33096483
DOI: 10.1016/j.ebiom.2020.103058 -
Cell Communication and Signaling : CCS Sep 2023Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis.... (Review)
Review
Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis. This phenomenon is called the "Warburg effect". Phosphoglycerate kinase 1 (PGK1) is a key enzyme in aerobic glycolysis. PGK1 is involved in glucose metabolism as well as a variety of biological activities, including angiogenesis, EMT, mediated autophagy initiation, mitochondrial metabolism, DNA replication and repair, and other processes related to tumorigenesis and development. Recently, an increasing number of studies have proven that PGK1 plays an important role in cancer. In this manuscript, we discussed the effects of the structure, function, molecular mechanisms underlying PGK1 regulation on the initiation and progression of cancer. Additionally, PGK1 is associated with chemotherapy resistance and prognosis in tumour patients. This review presents an overview of the different roles played by PGK1 during tumorigenesis, which will help in the design of experimental studies involving PGK1 and enhance the potential for the use of PGK1 as a therapeutic target in cancer. Video Abstract.
Topics: Humans; Phosphoglycerate Kinase; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Autophagy
PubMed: 37723547
DOI: 10.1186/s12964-023-01256-4 -
British Journal of Haematology Jan 2007Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon causes of hereditary non-spherocytic haemolytic anaemia (HNSHA). The gene encoding the... (Review)
Review
Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon causes of hereditary non-spherocytic haemolytic anaemia (HNSHA). The gene encoding the erythrocyte enzyme PGK1, is X-linked. Mutations of this gene may cause chronic haemolysis with or without mental retardation and they may cause myopathies, often with episodes of myoglobinuria, or a combination of these clinical manifestations. Twenty-six families have been described and in 20 of these the mutations are known. The reason for different clinical manifestations of mutations of the same gene remains unknown.
Topics: Anemia, Hemolytic, Congenital Nonspherocytic; Base Sequence; Genetic Diseases, X-Linked; Humans; Molecular Sequence Data; Mutation; Phosphoglycerate Kinase; Protein Conformation
PubMed: 17222195
DOI: 10.1111/j.1365-2141.2006.06351.x -
Open Biology Nov 2020Phosphoglycerate kinase (PGK) is a glycolytic enzyme that is well conserved among the three domains of life. PGK is usually a monomeric enzyme of about 45 kDa that... (Review)
Review
Phosphoglycerate kinase (PGK) is a glycolytic enzyme that is well conserved among the three domains of life. PGK is usually a monomeric enzyme of about 45 kDa that catalyses one of the two ATP-producing reactions in the glycolytic pathway, through the conversion of 1,3-bisphosphoglycerate (1,3BPGA) to 3-phosphoglycerate (3PGA). It also participates in gluconeogenesis, catalysing the opposite reaction to produce 1,3BPGA and ADP. Like most other glycolytic enzymes, PGK has also been catalogued as a moonlighting protein, due to its involvement in different functions not associated with energy metabolism, which include pathogenesis, interaction with nucleic acids, tumorigenesis progression, cell death and viral replication. In this review, we have highlighted the overall aspects of this enzyme, such as its structure, reaction kinetics, activity regulation and possible moonlighting functions in different protistan organisms, especially both free-living and parasitic Kinetoplastea. Our analysis of the genomes of different kinetoplastids revealed the presence of open-reading frames (ORFs) for multiple PGK isoforms in several species. Some of these ORFs code for unusually large PGKs. The products appear to contain additional structural domains fused to the PGK domain. A striking aspect is that some of these PGK isoforms are predicted to be catalytically inactive enzymes or 'dead' enzymes. The roles of PGKs in kinetoplastid parasites are analysed, and the apparent significance of the PGK gene duplication that gave rise to the different isoforms and their expression in is discussed.
Topics: Binding Sites; Catalysis; Enzyme Activation; Evolution, Molecular; Gene Expression Regulation, Enzymologic; Humans; Kinetoplastida; Models, Molecular; Phosphoglycerate Kinase; Phylogeny; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity
PubMed: 33234025
DOI: 10.1098/rsob.200302 -
Experimental Animals Nov 2023Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications...
Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100β in serum brain biomarkers' integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100β in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.
Topics: Rats; Animals; Phosphoglycerate Kinase; Vascular Endothelial Growth Factor A; Blood-Brain Barrier; Lithium; Pilocarpine; Angiostatins; Seizures; Epilepsy; Adenosine Triphosphate
PubMed: 37258131
DOI: 10.1538/expanim.23-0019 -
Aging Oct 2022Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. In the current study, we synthesized a PEP-1-PGK1...
Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. In the current study, we synthesized a PEP-1-PGK1 fusion protein that can cross the blood-brain barrier and cell membrane, and the effects of PEP-1-PGK1 against oxidative stress were investigated HT22 cells and ischemic gerbil brain. The PEP-1-PGK1 protein and its control protein (Con-PGK1) were treated and permeability was evaluated HT22 cells. The PEP-1-PGK1 was introduced into HT22 cells depending on its concentration and incubation time and was gradually degraded over 36 h after treatment. PEP-1-PGK1, but not Con-PGK1, significantly ameliorated HO-induced cell damage and reactive oxygen species formation in HT22 cells. Additionally, PEP-1-PGK1, but not Con-PGK1, mitigated ischemia-induced hyperlocomotion 1 d after ischemia and 4 d after ischemia of neuronic cell death. PEP-1-PGK1 treatment significantly alleviated the raised lactate and succinate dehydrogenase activities in the early (15 min to 6 h) and late (4 and 7 d) stages of ischemia, respectively. In addition, PEP-1-PGK1 treatment ameliorated the decrease in ATP and pH levels in the late stage (2-7 d) of ischemia. Nuclear factor erythroid-2-related factor 2 (Nrf2) levels accelerated the ischemia-induced increase in the hippocampus 1 d after ischemia after PEP-1-PGK1 treatment. Neuroprotective and ameliorative effects were prominent at a low concentration (0.1 mg/kg), but not at a high concentration (1 mg/kg), of PEP-1-PGK1. Collectively, low concentrations of PEP-1-PGK1 prevented neuronal stress by increasing energy production.
Topics: Animals; Gerbillinae; Phosphoglycerate Kinase; Hydrogen Peroxide; Hippocampus; Ischemia; Oxidative Stress
PubMed: 36260875
DOI: 10.18632/aging.204343