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Molecular Cell Feb 2022Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a...
Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.
Topics: Adenosine Triphosphate; Animals; Biomarkers, Tumor; Carrier Proteins; Cell Proliferation; DNA-Binding Proteins; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glycolysis; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; L-Lactate Dehydrogenase; Membrane Proteins; Mice, Nude; Multienzyme Complexes; Neoplasms; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-myc; RNA, Long Noncoding; Serine; Thyroid Hormones; Tumor Burden; Tumor Suppressor Proteins; Thyroid Hormone-Binding Proteins; Mice
PubMed: 35081364
DOI: 10.1016/j.molcel.2021.11.017 -
Hepatology (Baltimore, Md.) Jul 2022Hepatic ischemia-reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5)...
BACKGROUND AND AIMS
Hepatic ischemia-reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear.
APPROACH AND RESULTS
RNF5 expression was significantly down-regulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression of cell lines were subjected to hypoxia-reoxygenation challenge. Results showed that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, whereas RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of apoptosis-regulating kinase 1 (ASK1) and its downstream c-Jun N-terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR.
CONCLUSIONS
We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.
Topics: Animals; Apoptosis; Humans; Liver; Membrane Proteins; Mice; Phosphoprotein Phosphatases; Reperfusion Injury; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34735734
DOI: 10.1002/hep.32226 -
The Journal of Clinical Investigation Oct 2013Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain...
Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.
Topics: Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Line, Tumor; Cell Movement; Cell Survival; Deoxyglucose; Energy Metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycolysis; Hexokinase; Humans; Immunologic Memory; Immunotherapy, Active; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Stress, Physiological; T-Lymphocytes; Tumor Burden
PubMed: 24091329
DOI: 10.1172/JCI69589 -
Bone Research Mar 2024Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are...
Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of β-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.
Topics: Humans; Animals; Mice; Phosphoglycerate Mutase; beta Catenin; Osteoarthritis; Inflammation; Macrophages; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 38433252
DOI: 10.1038/s41413-024-00318-8 -
Cell Discovery Feb 2024Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R)...
Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.
PubMed: 38409220
DOI: 10.1038/s41421-023-00622-3 -
OncoTargets and Therapy 2020Phosphoglycerate mutase 1 (PGAM1) is an important enzyme that catalyzes the reversible conversion of 3-phosphoglycerate and 2-phosphoglycerate during the process of... (Review)
Review
Phosphoglycerate mutase 1 (PGAM1) is an important enzyme that catalyzes the reversible conversion of 3-phosphoglycerate and 2-phosphoglycerate during the process of glycolysis. Increasing evidence suggests that PGAM1 is widely overexpressed in various cancer tissues and plays a significant role in promoting cancer progression and metastasis. Although PGAM1 is a potential target in cancer therapy, the specific mechanisms of action remain unknown. This review introduces the basic structure and functions of PGAM1 and its family members and summarizes recent advances in the role of PGAM1 and various inhibitors of cancer cell proliferation and metastasis from a glycolytic and non-glycolytic perspective. Recent studies have highlighted a correlation between PGAM1 and clinical features and prognosis of cancer as well as the development of target drugs for PGAM1. The integrated information in this review will help better understand the specific roles of PGAM1 in cancer progression. Furthermore, the information highlights the non-glycolytic functions of PGAM1 in tumor metastasis, providing an innovative basis and direction for clinical drug research.
PubMed: 32161473
DOI: 10.2147/OTT.S238920 -
IUBMB Life Oct 2019Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to... (Review)
Review
Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer-specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.
Topics: Cell Proliferation; Glyceric Acids; Glycolysis; Humans; Molecular Targeted Therapy; Neoplasms; Phosphoglycerate Mutase
PubMed: 31169978
DOI: 10.1002/iub.2100 -
Neurotherapeutics : the Journal of the... Oct 2018Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL),... (Review)
Review
Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), β-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations.
Topics: Animals; Glycogen; Humans; Metabolic Diseases; Muscular Diseases
PubMed: 30397902
DOI: 10.1007/s13311-018-00684-2 -
Asian Journal of Andrology 2018Phosphoglycerate mutase 1 (PGAM1) is upregulated in many cancer types and involved in cell proliferation, migration, invasion, and apoptosis. However, the relationship...
Phosphoglycerate mutase 1 (PGAM1) is upregulated in many cancer types and involved in cell proliferation, migration, invasion, and apoptosis. However, the relationship between PGAM1 and prostate cancer is poorly understood. The present study investigated the changes in PGAM1 expression in prostate cancer tissues compared with normal prostate tissues and examined the cellular function of PGAM1 and its relationship with clinicopathological variables. Immunohistochemistry and Western blotting revealed that PGAM1 expression was upregulated in prostate cancer tissues and cell lines. PGAM1 expression was associated with Gleason score (P = 0.01) and T-stage (P = 0.009). Knockdown of PGAM1 by siRNA in PC-3 and 22Rv1 prostate cancer cell lines inhibited cell proliferation, migration, and invasion and enhanced cancer cell apoptosis. In a nude mouse xenograft model, PGAM1 knockdown markedly suppressed tumor growth. Deletion of PGAM1 resulted in decreased expression of Bcl-2, enhanced expression of Bax, caspases-3 and inhibition of MMP-2 and MMP-9 expression. Our results indicate that PGAM1 may play an important role in prostate cancer progression and aggressiveness, and that it might be a valuable marker of poor prognosis and a potential therapeutic target for prostate cancer.
Topics: Animals; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Deletion; Gene Knockdown Techniques; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; PC-3 Cells; Phosphoglycerate Mutase; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Transplantation, Heterologous; bcl-2-Associated X Protein
PubMed: 29271400
DOI: 10.4103/aja.aja_57_17 -
Drug Resistance Updates : Reviews and... May 2023Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the...
A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.
Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.
Topics: Humans; Erlotinib Hydrochloride; Lung Neoplasms; Interleukin-6; Phosphoglycerate Mutase; Drug Resistance, Neoplasm; Adenocarcinoma of Lung; ErbB Receptors; Signal Transduction; Protein Kinase Inhibitors; Mutation; Cell Line, Tumor; Janus Kinase 2
PubMed: 36990047
DOI: 10.1016/j.drup.2023.100957