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American Journal of Reproductive... Jun 2022Placentae from patients with preeclampsia have increased susceptibility to necroptosis and phosphoglycerate mutase 5 (PGAM5) plays a role in many necrosis pathways. We...
OBJECTIVES
Placentae from patients with preeclampsia have increased susceptibility to necroptosis and phosphoglycerate mutase 5 (PGAM5) plays a role in many necrosis pathways. We determined whether PGAM5 promotes necroptosis of trophoblast cells and the underlying mechanisms in this study.
METHODS
The injury model was established by treating JEG3 cells with hypoxia for 24 h. The functional measurements were assessed by the cell counting kit-8, propidium iodide (PI)/Annexin V staining, JC-1 staining and firefly luciferase ATP assay. The expression of proteins in human placentae and JEG3 cells was measured Western blot. PGAM5 was knocked down to study its role in hypoxia-induced necroptosis.
RESULTS
The placentae from patients with preeclampsia showed up-regulation of PGAM5 and decreased levels of p-Drp1-S637, accompanied by increased necroptosis-relevant proteins expression. The expression of PGAM5 in JEG3 cells was up-regulated under hypoxia, which promoted dephosphorylation of Drp1 at Serine 637 residue, mitochondrial dysfunction (elevated ROS level and reduced mitochondrial membrane potential and ATP content) and cellular necroptosis (increased PI /Annexin V cells and decreased cell viability), accompanied by increased expression of necroptosis-relevant proteins; knockdown of PGAM5 attenuated these phenomena.
CONCLUSIONS
Our results indicate that PGAM5 can promote necroptosis in trophoblast cells through, at least in part, activation of Drp1. It may be used as a new therapeutic target to prevent trophoblast dysfunction in preeclampsia.
Topics: Adenosine Triphosphate; Annexin A5; Cell Line, Tumor; Dynamins; Female; Humans; Hypoxia; Necroptosis; Phosphoglycerate Mutase; Phosphoprotein Phosphatases; Pre-Eclampsia; Pregnancy; Trophoblasts
PubMed: 35304783
DOI: 10.1111/aji.13539 -
Cell Reports Apr 2020The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the...
The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA Damage; DNA Repair; Female; Humans; Male; Mice; Phosphoglycerate Mutase; Protein Phosphatase 2C
PubMed: 32294440
DOI: 10.1016/j.celrep.2020.03.082 -
Journal of Clinical Laboratory Analysis Nov 2022To identify a novel marker for gastric cancer, we examined the usefulness of phosphoglycerate mutase 1 (PGAM1) as a potential diagnostic marker using isobaric tags for...
BACKGROUND
To identify a novel marker for gastric cancer, we examined the usefulness of phosphoglycerate mutase 1 (PGAM1) as a potential diagnostic marker using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and evaluated its clinical significance.
METHODS
Proteins from a discovery group of four paired gastric cancer tissues and adjacent gastric tissues were labeled with iTRAQ reagents and then identified and quantified using LC-MS/MS. The expression of PGAM1 was further validated in 139 gastric cancer patients using immunohistochemistry. Furthermore, the correlation of PGAM1 expression with clinical parameters was analyzed. Gene set enrichment analysis (GSEA) was performed to identify gene sets that were activated in PGAM1-overexpressing patients with gastric cancer.
RESULTS
PGAM1 was significantly overexpressed in most cancers but particularly so in gastric cancer, with a sensitivity of 82.01% (95% confidence interval [CI]: 75.5%-88.5%) and specificity of 79.13% (95% CI: 72.3%-86%). Its expression was significantly associated with histological grade II and III tumors (p = 0.033), lymph node metastasis (p = 0.031), and TNM III-IV staging (p = 0.025). The area under the receiver operating characteristic (ROC) curve for the detection of PGAM1 overexpression in gastric cancer was 0.718 (p < 0.01). Furthermore, GSEA revealed that several important pathways such as glycolysis pathway and immune pathways were significantly enriched in patients with gastric cancer with PGAM1 overexpression.
CONCLUSIONS
This study provided a sensitive method for detecting PGAM1, which may serve as a novel indicator for poor prognosis of gastric cancer, as well as a potent drug target for gastric cancer.
Topics: Humans; Phosphoglycerate Mutase; Stomach Neoplasms; Chromatography, Liquid; Tandem Mass Spectrometry; Glycolysis; Neoplasm Staging
PubMed: 36181311
DOI: 10.1002/jcla.24718 -
Advanced Science (Weinheim,... Oct 2023The combination of immunotherapy and molecular targeted therapy exhibits promising therapeutic efficacy in hepatocellular carcinoma (HCC), but the underlying mechanism...
The combination of immunotherapy and molecular targeted therapy exhibits promising therapeutic efficacy in hepatocellular carcinoma (HCC), but the underlying mechanism is still unclear. Here, phosphoglycerate mutase 1 (PGAM1) is identified as a novel immunometabolic target by using a bioinformatic algorithm based on multiple HCC datasets. PGAM1 is highly expressed in HCC and associated with a poor prognosis and a poor response to immunotherapy. In vitro and in vivo experiments indicate that targeting PGAM1 inhibited HCC cell growth and promoted the infiltration of CD8 T-cells due to decreased enzymatic activity. Mechanistically, inhibition of PGAM1 promotes HCC cell ferroptosis by downregulating Lipocalin (LCN2) by inducing energy stress and ROS-dependent AKT inhibition, which can also downregulate Programmed death 1-ligand 1 (PD-L1). Moreover, an allosteric PGAM1 inhibitor (KH3) exhibits good antitumor effects in patient-derived xenograft (PDX) models and enhanced the efficacy of anti-PD-1 immunotherapy in subcutaneous and orthotopic HCC models. Taken together, the findings demonstrate that PGAM1 inhibition exerts an antitumor effect by promoting ferroptosis and CD8 T-cell infiltration and can synergize with anti-PD-1 immunotherapy in HCC. Targeting PGAM1 can be a promising new strategy of "killing two birds with one stone" for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Phosphoglycerate Mutase; CD8-Positive T-Lymphocytes; Ferroptosis; Immunotherapy
PubMed: 37705495
DOI: 10.1002/advs.202301928 -
International Journal of Cancer Nov 2014A significant characteristic of cancer cell metabolism is the high level of aerobic glycolysis with high glucose consumption and lactate production. Phophoglycerate... (Review)
Review
A significant characteristic of cancer cell metabolism is the high level of aerobic glycolysis with high glucose consumption and lactate production. Phophoglycerate mutase 1 (PGAM1) is an enzyme that catalyzes the interconversion of 3-phosphoglycerate and 2-phosphoglycerate during glycolysis. It has been reported that this enzyme is commonly upregulated in many human cancers. PGAM1 plays an important role in coordinating glycolysis and anabolic activity to promote cancer cell proliferation. However, the mechanisms under these effects are still poorly understood. This review focuses on the most recent advances in the structure and functions of PGAM1, and PGAM1's role in glycolysis in cancer cells and regulators that modulate PGAM1's effects. Progress in understanding of PGAM1 will provide the rationale to support the development of new hypothesis-driven studies to define PGAM1's potential therapeutic implications for cancer treatment.
Topics: Animals; Antineoplastic Agents; Glycolysis; Humans; Neoplasms; Oxygen; Phosphoglycerate Mutase
PubMed: 24285383
DOI: 10.1002/ijc.28637 -
Current Topics in Medicinal Chemistry 2018Nowadays, malaria is still one of the most important and lethal diseases worldwide, causing 445,000 deaths in a year. Due to the actual treatment resistance, there is an... (Review)
Review
BACKGROUND
Nowadays, malaria is still one of the most important and lethal diseases worldwide, causing 445,000 deaths in a year. Due to the actual treatment resistance, there is an emergency to find new drugs.
OBJECTIVE
The aim of this work was to find potential inhibitors of phosphoglycerate mutase 1 from P. falciparum.
RESULTS
Through virtual screening of a chemical library of 15,123 small molecules, analyzed by two programs, four potential inhibitors of phosphoglycerate mutase 1 from P. falciparum were found: ZINC64219552, ZINC39095354, ZINC04593310, and ZINC04343691; their binding energies in SP mode were -7.3, -7.41, -7.4, and -7.18 kcal/mol respectively. Molecular dynamic analysis revealed that these molecules interact with residues important for enzyme catalysis and molecule ZINC04343691 provoked the highest structural changes. Physiochemical and toxicological profiles evaluation of these inhibitors with ADME-Tox method suggested that they can be considered as potential drugs. Furthermore, analysis of human PGAM-B suggested that these molecules could be selective for the parasitic enzyme.
CONCLUSION
The compounds reported here are the first selective potential inhibitors of phosphoglycerate mutase 1 from P. falciparum, and can serve as a starting point in the search of a new chemotherapy against malaria.
Topics: Drug Evaluation, Preclinical; Enzyme Inhibitors; Ligands; Molecular Dynamics Simulation; Phosphoglycerate Mutase; Plasmodium falciparum; Small Molecule Libraries; Software
PubMed: 30370850
DOI: 10.2174/1568026618666181029144653 -
ACS Chemical Biology Mar 2020Post-translational modifications play vital roles in fine-tuning a myriad of physiological processes, and one of the most important modifications is acetylation. Here,...
Post-translational modifications play vital roles in fine-tuning a myriad of physiological processes, and one of the most important modifications is acetylation. Here, we report a ligand-directed site-selective acetylation using KHAc, a derivative of a phosphoglycerate mutase 1 (PGAM1) inhibitor. KHAc binds to PGAM1 and transfers its acetyl group to the ε-NH of Lys100 to inactivate the enzyme. The acetyl transfer process was visualized by time-resolved crystallography, demonstrating that the transfer is driven by proximity effects. KHAc was capable of selectively and effectively acetylating Lys100 of PGAM1 in cultured human cells, accompanied by inhibited F-actin formation. Similar strategies could be used for exogenous control of other lysine post-translational modifications.
Topics: Acetylation; Actins; Binding Sites; Cell Proliferation; Crystallization; Enzyme Inhibitors; HEK293 Cells; Heterocyclic Compounds; Humans; Ligands; Mutation; Phosphoglycerate Mutase; Protein Binding; Protein Conformation; Protein Processing, Post-Translational
PubMed: 32069008
DOI: 10.1021/acschembio.9b00962 -
Cell Reports Aug 2023Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and...
Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.
Topics: GTP Phosphohydrolases; Phosphoric Monoester Hydrolases; Phosphoglycerate Mutase; Mitochondrial Dynamics; Mitochondrial Proteins; Dynamins
PubMed: 37498743
DOI: 10.1016/j.celrep.2023.112895 -
Ryoikibetsu Shokogun Shirizu 1998
Review
Topics: Humans; Kidney Diseases; Muscular Diseases; Mutation; Myoglobinuria; Phosphoglycerate Mutase; Prognosis
PubMed: 9589993
DOI: No ID Found -
Cell Death & Disease Aug 2023Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the...
Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the underlying mechanism of exosomal PGAM1 in prostate cancer (PCa) metastasis remains unclear. In this study, we performed in vitro and in vivo to determine the functions of exosomal PGAM1 in the angiogenesis of patients with metastatic PCa. We performed Glutathione-S-transferase pulldown, co-immunoprecipitation, western blotting and gelatin degradation assays to determine the pathway mediating the effect of exosomal PGAM1 in PCa. Our results revealed a significant increase in exosomal PGAM1 levels in the plasma of patients with metastatic PCa compared to patients with non-metastatic PCa. Furthermore, PGAM1 was a key factor initiating PCa cell metastasis by promoting invadopodia formation and could be conveyed by exosomes from PCa cells to human umbilical vein endothelial cells (HUVECs). In addition, exosomal PGAM1 could bind to γ-actin (ACTG1), which promotes podosome formation and neovascular sprouting in HUVECs. In vivo results revealed exosomal PGAM1 enhanced lung metastasis in nude mice injected with PCa cells via the tail vein. In summary, exosomal PGAM1 promotes angiogenesis and could be used as a liquid biopsy marker for PCa metastasis.
Topics: Animals; Humans; Male; Mice; Actins; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Exosomes; Mice, Nude; MicroRNAs; Neoplasm Metastasis; Phosphoglycerate Mutase; Prostatic Neoplasms
PubMed: 37542027
DOI: 10.1038/s41419-023-06007-4