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Journal of Cellular Physiology Aug 2022Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in...
Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in diastolic dysfunction. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism and heart failure (HF). In the present study, we investigated the role of TIGAR in diastolic function and cardiac fibrosis during pressure overload (PO)-induced HF. WT mice subjected to transverse aortic constriction (TAC), a commonly used method to induce diastolic dysfunction, exhibited diastolic dysfunction as evidenced by increased E/A ratio and E/E' ratio when compared to its sham controls. This was accompanied by increased cardiac interstitial fibrosis. In contrast, the knockout of TIGAR attenuated PO-induced diastolic dysfunction and interstitial fibrosis. Mechanistically, the levels of glucose transporter Glut-1, Glut-4, and key glycolytic enzyme phosphofructokinase 1 (PFK-1) were significantly elevated in TIGAR KO subjected to TAC as compared to that of WT mice. Knockout of TIGAR significantly increased fructose 2,6-bisphosphate levels and phosphofructokinase activity in mouse hearts. In addition, PO resulted in a significant increase in perivascular fibrosis and endothelial activation in the WT mice, but not in the TIGAR KO mice. Our present study suggests a necessary role of TIGAR-mediated glucose metabolism in PO-induced cardiac fibrosis and diastolic dysfunction.
Topics: Animals; Apoptosis Regulatory Proteins; Diastole; Disease Models, Animal; Fibrosis; Glucose; Glycolysis; Heart Failure; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Phosphofructokinases; Phosphoric Monoester Hydrolases
PubMed: 35621078
DOI: 10.1002/jcp.30790 -
Cellular and Molecular Gastroenterology... 2023
Topics: Humans; Reactive Oxygen Species; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Liver Neoplasms; Cell Line, Tumor; Phosphofructokinase-2
PubMed: 36963434
DOI: 10.1016/j.jcmgh.2023.02.015 -
Annals of Botany Jan 2022ATP-dependent phosphofructokinases (PFKs) catalyse phosphorylation of the carbon-1 position of fructose-6-phosphate, to form fructose-1,6-bisphosphate. In the cytosol,...
BACKGROUND AND AIMS
ATP-dependent phosphofructokinases (PFKs) catalyse phosphorylation of the carbon-1 position of fructose-6-phosphate, to form fructose-1,6-bisphosphate. In the cytosol, this is considered a key step in channelling carbon into glycolysis. Arabidopsis thaliana has seven genes encoding PFK isoforms, two chloroplastic and five cytosolic. This study focuses on the four major cytosolic isoforms of PFK in vegetative tissues of A. thaliana.
METHODS
We isolated homozygous knockout individual mutants (pfk1, pfk3, pfk6 and pfk7) and two double mutants (pfk1/7 and pfk3/6), and characterized their growth and metabolic phenotypes.
KEY RESULTS
In contrast to single mutants and the double mutant pfk3/6 for the hypoxia-responsive isoforms, the double mutant pfk1/7 had reduced PFK activity and showed a clear visual and metabolic phenotype with reduced shoot growth, early flowering and elevated hexose levels. This mutant also has an altered ratio of short/long aliphatic glucosinolates and an altered root-shoot distribution. Surprisingly, this mutant does not show any major changes in short-term carbon flux and in levels of hexose-phosphates.
CONCLUSIONS
We conclude that the two isoforms PFK1 and PFK7 are important for sugar homeostasis in leaf metabolism and apparently in source-sink relationships in A. thaliana, while PFK3 and PFK6 only play a minor role under normal growth conditions.
Topics: Arabidopsis; Arabidopsis Proteins; Cytosol; Homeostasis; Phosphofructokinases; Plant Leaves; Sugars
PubMed: 34549262
DOI: 10.1093/aob/mcab122 -
World Journal of Gastroenterology Oct 2014Enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 and -4 (PFKFB-3 and PFKFB-4) play a significant role in the regulation of glycolysis in cancer cells as... (Review)
Review
Enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 and -4 (PFKFB-3 and PFKFB-4) play a significant role in the regulation of glycolysis in cancer cells as well as its proliferation and survival. The expression of these mRNAs is increased in malignant tumors and strongly induced in different cancer cell lines by hypoxia inducible factor (HIF) through active HIF binding sites in promoter region of PFKFB-4 and PFKFB-3 genes. Moreover, the expression and hypoxia responsibility of PFKFB-4 and PFKFB-3 was also shown for pancreatic (Panc1, PSN-1, and MIA PaCa-2) as well as gastric (MKN45 and NUGC3) cancer cells. At the same time, their basal expression level and hypoxia responsiveness vary in the different cells studied: the highest level of PFKFB-4 protein expression was found in NUGC3 gastric cancer cell line and lowest in Panc1 cells, with a stronger response to hypoxia in the pancreatic cancer cell line. Overexpression of different PFKFB in pancreatic and gastric cancer cells under hypoxic condition is correlated with enhanced expression of vascular endothelial growth factor (VEGF) and Glut1 mRNA as well as with increased level of HIF-1α protein. Increased expression of different PFKFB genes was also demonstrated in gastric, lung, breast, and colon cancers as compared to corresponding non-malignant tissue counterparts from the same patients, being more robust in the breast and lung tumors. Moreover, induction of PFKFB-4 mRNA expression in the breast and lung cancers is stronger than PFKFB-3 mRNA. The levels of both PFKFB-4 and PFKFB-3 proteins in non-malignant gastric and colon tissues were more pronounced than in the non-malignant breast and lung tissues. It is interesting to note that Panc1 and PSN-1 cells transfected with dominant/negative PFKFB-3 (dnPFKFB-3) showed a lower level of endogenous PFKFB-3, PFKFB-4, and VEGF mRNA expressions as well as a decreased proliferation rate of these cells. Moreover, a similar effect had dnPFKFB-4. In conclusion, there is strong evidence that PFKFB-4 and PFKFB-3 isoenzymes are induced under hypoxia in pancreatic and other cancer cell lines, are overexpressed in gastric, colon, lung, and breast malignant tumors and undergo changes in their metabolism that contribute to the proliferation and survival of cancer cells. Thus, targeting these PFKFB may therefore present new therapeutic opportunities.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Drug Design; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Pancreatic Neoplasms; Phosphofructokinase-2; RNA, Messenger; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment
PubMed: 25320508
DOI: 10.3748/wjg.v20.i38.13705 -
Journal of Hazardous Materials Feb 2024Exposure to ambient ultrafine particulate matter (UPM) causes respiratory disorders; however, the underlying molecular mechanisms remain unclear. In this study, we...
Exposure to ambient ultrafine particulate matter (UPM) causes respiratory disorders; however, the underlying molecular mechanisms remain unclear. In this study, we synthesized simulated UPM (sUPM) with controlled physicochemical properties using the spark-discharge method. Subsequently, we investigated the biological effects of sUPM using BEAS-2B human bronchial epithelial cells (HBECs) and a mouse intratracheal instillation model. High throughput RNA-sequencing and bioinformatics analyses revealed that dysregulation of the glycolytic metabolism is involved in the inhibited proliferation and survival of HBECs by sUPM treatment. Furthermore, signaling pathway and enzymatic analyses showed that the treatment of BEAS-2B cells with sUPM induces the inactivation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB, also known as AKT), resulting in the downregulation of phosphofructokinase 2 (PFK2) S483 phosphorylation, PFK enzyme activity, and aerobic glycolysis in HBECs in an oxidative stress-independent manner. Additionally, intratracheal instillation of sUPM reduced the phosphorylation of ERK, AKT, and PFK2, decreased proliferation, and increased the apoptosis of bronchial epithelial cells in mice. The findings of this study imply that UPM induces pulmonary toxicity by disrupting aerobic glycolytic metabolism in lung epithelial cells, which can provide novel insights into the toxicity mechanisms of UPM and strategies to prevent their toxic effects.
Topics: Humans; Animals; Mice; Particulate Matter; Proto-Oncogene Proteins c-akt; Phosphorylation; Epithelial Cells; Glycolysis; Phosphofructokinases; Air Pollutants
PubMed: 37976851
DOI: 10.1016/j.jhazmat.2023.132966 -
Open Biology Oct 2023The human formyl-peptide receptor 2 (FPR2) is activated by an array of ligands. By phospho-proteomic analysis we proved that FPR2 stimulation induces redox-regulated...
The human formyl-peptide receptor 2 (FPR2) is activated by an array of ligands. By phospho-proteomic analysis we proved that FPR2 stimulation induces redox-regulated phosphorylation of many proteins involved in cellular metabolic processes. In this study, we investigated metabolic pathways activated in FPR2-stimulated CaLu-6 cells. The results showed an increased concentration of metabolites involved in glucose metabolism, and an enhanced uptake of glucose mediated by GLUT4, the insulin-regulated member of GLUT family. Accordingly, we observed that FPR2 transactivated IGF-IR/IR through a molecular mechanism that requires Nox2 activity. Since cancer cells support their metabolism via glycolysis, we analysed glucose oxidation and proved that FPR2 signalling promoted kinase activity of the bifunctional enzyme PFKFB2 through FGFR1/FRS2- and Akt-dependent phosphorylation. Furthermore, FPR2 stimulation induced IGF-IR/IR-, PI3K/Akt- and Nox-dependent inhibition of pyruvate dehydrogenase activity, thus preventing the entry of pyruvate in the tricarboxylic acid cycle. Consequently, we observed an enhanced FGFR-dependent lactate dehydrogenase (LDH) activity and lactate production in FPR2-stimulated cells. As LDH expression is transcriptionally regulated by c-Myc and HIF-1, we demonstrated that FPR2 signalling promoted c-Myc phosphorylation and Nox-dependent HIF-1 stabilization. These results strongly indicate that FPR2-dependent signalling can be explored as a new therapeutic target in treatment of human cancers.
Topics: Humans; Proto-Oncogene Proteins c-akt; Proteomics; Glucose; Phosphatidylinositol 3-Kinases; Oxidoreductases; Phosphofructokinase-2
PubMed: 37875162
DOI: 10.1098/rsob.230336 -
Journal of Leukocyte Biology Feb 2024The August 2023 article in Science Signaling, "TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis," challenges the...
The August 2023 article in Science Signaling, "TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis," challenges the traditional M1/M2 macrophage classification by investigating the impact of transforming growth factor β on macrophage metabolism and function. Despite its conventional anti-inflammatory role, transforming growth factor β-treated macrophages exhibit a distinct phenotype marked by heightened glycolysis, suppressed proinflammatory cytokines, and increased coagulation factor expression. The study identifies phosphofructokinase, liver type as a crucial glycolytic enzyme regulated by transforming growth factor β via the mTOR-c-MYC pathway. Epigenetic changes induced by transforming growth factor β, such as increased Smad3 activation and reduced proinflammatory transcription factor motif enrichment, contribute to the anti-inflammatory profile. The research extends its implications to sepsis, revealing the role of transforming growth factor β in exacerbating coagulation and reducing survival in mouse models. This effect involves upregulation of coagulation factor F13A1, dependent on phosphofructokinase, liver type activity and glycolysis in macrophages. Connections to COVID-19 pathology are drawn, as transforming growth factor β-treated macrophages and SARS-CoV-2 E protein-exposed cells display similar metabolic profiles. Bioinformatic analysis of COVID-19 patient data suggests correlations between myeloid expression of TGFβR1, PFKL, and F13A1 with disease severity. The study challenges the M1/M2 classification, emphasizing the complexity of macrophage responses influenced by transforming growth factor β, proposing transforming growth factor β as a potential therapeutic target for conditions like sepsis and COVID-19 where dysregulated coagulation is significant. Overall, the research provides valuable insights into transforming growth factor β-mediated immunometabolic regulation, paving the way for future investigations and potential therapeutic interventions.
Topics: Mice; Animals; Humans; Transforming Growth Factor beta; Macrophages; Sepsis; Anti-Inflammatory Agents; Phosphofructokinases; Blood Coagulation Factors; COVID-19; Macrophage Activation
PubMed: 38197509
DOI: 10.1093/jleuko/qiae001 -
Scientific Reports Mar 2021Glutamine:fructose-6-phosphate aminotransferase (GFAT) and phosphofructokinase (PFK) are enzymes related to chitin metabolism. RNA interference (RNAi) technology was...
Glutamine:fructose-6-phosphate aminotransferase (GFAT) and phosphofructokinase (PFK) are enzymes related to chitin metabolism. RNA interference (RNAi) technology was used to explore the role of these two enzyme genes in chitin metabolism. In this study, we found that GFAT and PFK were highly expressed in the wing bud of Nilaparvata lugens and were increased significantly during molting. RNAi of GFAT and PFK both caused severe malformation rates and mortality rates in N. lugens. GFAT inhibition also downregulated GFAT, GNPNA, PGM1, PGM2, UAP, CHS1, CHS1a, CHS1b, Cht1-10, and ENGase. PFK inhibition significantly downregulated GFAT; upregulated GNPNA, PGM2, UAP, Cht2-4, Cht6-7 at 48 h and then downregulated them at 72 h; upregulated Cht5, Cht8, Cht10, and ENGase; downregulated Cht9 at 48 h and then upregulated it at 72 h; and upregulated CHS1, CHS1a, and CHS1b. In conclusion, GFAT and PFK regulated chitin degradation and remodeling by regulating the expression of genes related to the chitin metabolism and exert opposite effects on these genes. These results may be beneficial to develop new chitin synthesis inhibitors for pest control.
Topics: Animals; Chitin; Chitin Synthase; Gene Expression Regulation; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Hemiptera; Insect Proteins; Phosphofructokinases; RNA Interference
PubMed: 33664411
DOI: 10.1038/s41598-021-84760-2 -
Molecular Biology Reports Oct 2020Rapid utilization of glucose is a functional marker of cancer cells, and has been exploited in the clinical diagnosis of malignancies using imaging technology.... (Review)
Review
Rapid utilization of glucose is a functional marker of cancer cells, and has been exploited in the clinical diagnosis of malignancies using imaging technology. Biochemically, an increase in the rate of glycolysis, (i.e.) the process of conversion of glucose into pyruvate accelerates the net rate of glucose consumption. One of the critical determinants of glycolytic flux is the enzyme, phosphofructokinase (PFK) which converts fructose-6-phosphate into fructose 1,6, bisphosphate. PFK activity is allosterically inhibited or upregulated by cellular ATP or AMP, respectively. In a recent report of Cellular Oncology, Shen et al., have investigated one of the forms of PFK known as the platelet-type PFK (PFKP) in lung cancer. Using clinical samples as well as experimental models the authors unravel the cancer-related roles of PFKP and demonstrate that PFKP phenotype may predict the prognosis of lung cancer. In this letter, the findings are discussed in the light of recent research to expand the potential application and clinical impact of PFKP phenotype in lung cancer.
Topics: Biomarkers, Tumor; Humans; Lung Neoplasms; Phosphofructokinase-1, Type C; Prognosis
PubMed: 32915402
DOI: 10.1007/s11033-020-05805-9 -
Cells Sep 2020Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell...
Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell survival, especially in metastatic cancer progression. Epithelial-mesenchymal transition (EMT) plays an important role in metabolic rewiring of cancer cells as well as in phenotypic conversion and therapeutic resistance. Snail (SNAI1), a well-known inducer of cancer EMT, is critical in providing ATP and NADPH via suppression of several gatekeeper genes involving catabolic metabolism, such as phosphofructokinase 1 (PFK1), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase 2 (ACC2). Paradoxically, PFK1 and FBP1 are counter-opposing and rate-limiting reaction enzymes of glycolysis and gluconeogenesis, respectively. In this study, we report a distinct metabolic circuit of catabolic metabolism in breast cancer subtypes. Interestingly, PFKP and FBP1 are inversely correlated in clinical samples, indicating different metabolic subsets of breast cancer. The luminal types of breast cancer consist of the pentose phosphate pathway (PPP) subset by suppression of PFKP while the basal-like subtype (also known as triple negative breast cancer, TNBC) mainly utilizes glycolysis and mitochondrial fatty acid oxidation (FAO) by loss of FBP1 and ACC2. Notably, PPP remains active via upregulation of TIGAR in the FBP1-loss basal-like subset, indicating the importance of PPP in catabolic cancer metabolism. These results indicate different catabolic metabolic circuits and thus therapeutic strategies in breast cancer subsets.
Topics: Acetyl-CoA Carboxylase; Adenosine Triphosphate; Breast Neoplasms; Cell Survival; Epithelial-Mesenchymal Transition; Female; Fructose-Bisphosphatase; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; NADP; Oxidation-Reduction; Pentose Phosphate Pathway; Phosphofructokinase-1, Type C; Snail Family Transcription Factors; Triple Negative Breast Neoplasms
PubMed: 32927665
DOI: 10.3390/cells9092064