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OPINION STATEMENT: Relapse after chemotherapy and hematopoietic stem cell transplantation leads to adverse prognosis for acute myeloid leukemia (AML) patients. As a "conditionally essential amino acid," glutamine contributes to the growth and proliferation of AML cells. Glutamine-target strategies as new treatment approaches have been widely explored in AML treatment to improve outcome. Glutamine-target strategies including depletion of systemic glutamine and application of glutamine uptake inhibitors, glutamine antagonists/analogues, and glutaminase inhibitors. Because glutamine metabolism involved in multiple pathways in cells and each pathway of glutamine metabolism has many regulatory factors, therefore, AML therapy targeting glutamine metabolism should focus on how to inhibit multiple metabolic pathways without affecting normal cells and host immune to achieve effective treatment for AML.
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Glutamina , Leucemia Mieloide Aguda , Humanos , Glutamina/metabolismo , Glutamina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
BACKGROUND: Glutamine serves as an important nutrient with many cancer types displaying glutamine dependence. Following cellular uptake glutamine is converted to glutamate in a reaction catalysed by mitochondrial glutaminase. This glutamate has many uses, including acting as an anaplerotic substrate (via alpha-ketoglutarate) to replenish TCA cycle intermediates. CB-839 is a potent, selective, orally bioavailable inhibitor of glutaminase that has activity in Triple receptor-Negative Breast Cancer (TNBC) cell lines and evidence of efficacy in advanced TNBC patients. METHODS: A panel of eleven breast cancer cell lines was used to investigate the anti-proliferative effects of the glutaminase inhibitors CB-839 and BPTES in different types of culture medium, with or without additional pyruvate supplementation. The abundance of the TCA cycle intermediate fumarate was quantified as a measure if TCA cycle anaplerosis. Pyruvate secretion by TNBC cultures was then assessed with or without AZD3965, a monocarboxylate transporter 1 (MCT1) inhibitor. Finally, two dimensional (2D) monolayer and three dimensional (3D) spheroid assays were used to compare the effect of microenvironmental growth conditions on CB-839 activity. RESULTS: The anti-proliferative activity of CB-839 in a panel of breast cancer cell lines was similar to published reports, but with a major caveat; growth inhibition by CB-839 was strongly attenuated in culture medium containing pyruvate. This pyruvate-dependent attenuation was also observed with a related glutaminase inhibitor, BPTES. Studies demonstrated that exogenous pyruvate acted as an anaplerotic substrate preventing the decrease of fumarate in CB-839-treated conditions. Furthermore, endogenously produced pyruvate secreted by TNBC cell lines was able to act in a paracrine manner to significantly decrease the sensitivity of recipient cells to glutaminase inhibition. Suppression of pyruvate secretion using the MCT1 inhibitor AZD3965, antagonised this paracrine effect and increased CB-839 activity. Finally, CB-839 activity was significantly compromised in 3D compared with 2D TNBC culture models, suggesting that 3D microenvironmental features impair glutaminase inhibitor responsiveness. CONCLUSION: This study highlights the potential influence that both circulating and tumour-derived pyruvate can have on glutaminase inhibitor efficacy. Furthermore, it highlights the benefits of 3D spheroid cultures to model the features of the tumour microenvironment and improve the in vitro investigation of cancer metabolism-targeted therapeutics.
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Benzenoacetamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glutaminase/antagonistas & inibidores , Glutamina/metabolismo , Ácido Pirúvico/metabolismo , Tiadiazóis/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
INTRODUCTION: Glutaminase inhibitors target cancer cells by blocking the conversion of glutamine to glutamate, thereby potentially interfering with anaplerosis and synthesis of amino acids and glutathione. The drug CB-839 has shown promising effects in preclinical experiments and is currently undergoing clinical trials in several human malignancies, including triple-negative breast cancer (TNBC). However, response to glutaminase inhibitors is variable and there is a need for identification of predictive response biomarkers. The aim of this study was to determine how glutamine is utilized in two patient-derived xenograft (PDX) models of breast cancer representing luminal-like/ER+ (MAS98.06) and basal-like/triple-negative (MAS98.12) breast cancer and to explore the metabolic effects of CB-839 treatment. EXPERIMENTAL: MAS98.06 and MAS98.12 PDX mice received CB-839 (200 mg/kg) or drug vehicle two times daily p.o. for up to 28 days (n = 5 per group), and the effect on tumor growth was evaluated. Expression of 60 genes and seven glutaminolysis key enzymes were determined using gene expression microarray analysis and immunohistochemistry (IHC), respectively, in untreated tumors. Uptake and conversion of glutamine were determined in the PDX models using HR MAS MRS after i.v. infusion of [5-13C] glutamine when the models had received CB-839 (200 mg/kg) or vehicle for 2 days (n = 5 per group). RESULTS: Tumor growth measurements showed that CB-839 significantly inhibited tumor growth in MAS98.06 tumors, but not in MAS98.12 tumors. Gene expression and IHC analysis indicated a higher proline synthesis from glutamine in untreated MAS98.06 tumors. This was confirmed by HR MAS MRS of untreated tumors demonstrating that MAS98.06 used glutamine to produce proline, glutamate, and alanine, and MAS98.12 to produce glutamate and lactate. In both models, treatment with CB-839 resulted in accumulation of glutamine. In addition, CB-839 caused depletion of alanine, proline, and glutamate ([1-13C] glutamate) in the MAS98.06 model. CONCLUSION: Our findings indicate that TNBCs may not be universally sensitive to glutaminase inhibitors. The major difference in the metabolic fate of glutamine between responding MAS98.06 xenografts and non-responding MAS98.12 xenografts is the utilization of glutamine for production of proline. We therefore suggest that addiction to proline synthesis from glutamine is associated with response to CB-839 in breast cancer. The effect of glutaminase inhibition in two breast cancer patient-derived xenograft (PDX) models. 13C HR MAS MRS analysis of tumor tissue from CB-839-treated and untreated models receiving 13C-labeled glutamine ([5-13C] Gln) shows that the glutaminase inhibitor CB-839 is causing an accumulation of glutamine (arrow up) in two PDX models representing luminal-like breast cancer (MAS98.06) and basal-like breast cancer (MAS98.12). In MAS98.06 tumors, CB-839 is in addition causing depletion of proline ([5-13C] Pro), alanine ([1-13C] Ala), and glutamate ([1-13C] Glu), which could explain why CB-839 causes tumor growth inhibition in MAS98.06 tumors, but not in MAS98.12 tumors.
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Neoplasias da Mama/metabolismo , Glutaminase/metabolismo , Glutamina/metabolismo , Prolina/metabolismo , Animais , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Perfilação da Expressão Gênica , Glutaminase/antagonistas & inibidores , Humanos , Imuno-Histoquímica , Espectroscopia de Ressonância Magnética , Metabolômica/métodos , Camundongos , Modelos Biológicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
JAK2(V617F) mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2(V617F)-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2(WT) cells and there was an increased glutamine metabolism in JAK2(V617F)-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in glutamine metabolism, was upregulated in the JAK2(V617F)-mutant BaF3 cells compared to the JAK2(WT) BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2(V617F)-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2(V617F)-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity.
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Glutamina/metabolismo , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/metabolismo , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Mutação , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Regulação para CimaRESUMO
The overexpression of glutaminase is reported to influence cancer growth and metastasis through glutaminolysis. Upregulation of glutamine catabolism is recently recognized as a critical feature of cancer, and cancer cells are observed to reprogram glutamine metabolism to maintain its survival and proliferation. Special focus is given on the glutaminase isoform, GLS1 (kidney type glutaminase), as the other isoform GLS2 (Liver type glutaminase) acts as a tumour suppressor in some conditions. Glutaminolysis linked with autophagy, which is mediated via mTORC1, also serves as a promising target for cancer therapy. Glutamine also plays a vital role in maintaining redox homeostasis. Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.
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This study was to compare glutaminase and Na+, K+-ATPase inhibitory activities of 20 herbal extracts and investigate the isolation, structural elucidation and those inhibitory activities of three triterpenes from the selected extract of Eucalyptus globulus Labill. Three triterpenes, ursolic acid (1), robustanic acid (2) and ursolic acid lactone (3), were identified by analyzing their NMR and MS spectral data and comparison of these with reported data. The IC50 values of 1-3 and the control compound against glutaminase, 6-diazo-5-oxo-l-norleucine (DON), were 443⯵M, 334⯵M, 963⯵M and 134⯵M, respectively. The IC50 values of 1, 2 and the control compound against Na+, K+-ATPase and ouabain, were 180⯵M, 56⯵M and 0.5⯵M, respectively. Compounds 1 and 2 may serve as potential lead compounds for the prevention and treatment of neurodegenerative and lifestyle-related diseases by targeting glutaminase and Na+, K+-ATPase. This is the first report on glutaminase and Na+, K+-ATPase inhibitory activities of 2.
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This study was to compare GABase [a mixture of γ-aminobutyric acid (GABA) aminotransferase and succinic semialdehyde dehydrogenase] and glutaminase inhibitory activities of 20 herbal extracts and investigate the isolation, structural elucidation and those inhibitory activities of three acylated flavonol monoglycosides from the selected extract of Laurus nobilis L. (laurel). On the basis of the NMR spectroscopic data and the ESI MS spectra together with the comparison with the literature values, three compounds were identified as kaempferol-3-O-(4â³-E-p-coumaroyl)-α-l-rhamnopyranoside (1), kaempferol-3-O-(3â³,4â³-di-E-p-coumaroyl)-α-l-rhamnopyranoside (2) and kaempferol-3-O-(2â³,4â³-di-E-p-coumaroyl)-α-l-rhamnopyranoside (3), respectively. The IC50 values of GABase inhibitory activity of 1-3 and p-hydroxybenzaldehyde (HBA) as control were 0.24â¯mM, 0.14â¯mM, 0.12â¯mM and 0.43â¯mM, respectively. Additionally, the IC50 values of glutaminase inhibitory activity of 1-3 and 6-diazo-5-oxo-l-norleucine (DON) as control were 0.34â¯mM, 0.13â¯mM, 0.14â¯mM and 0.33â¯mM, respectively. The results suggest that the extract from laurel shows the strongest biological activities among 20 herbal extracts and three acylated flavonol monoglycosides may serve as potential lead compounds for the prevention and treatment of neurodegenerative and lifestyle-related diseases by targeting GABase and glutaminase. This is the first report on GABase and glutaminase inhibitory activities of 1-3.
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Quempferóis , Laurus , Laurus/química , Glutaminase/análise , Extratos Vegetais/química , Flavonóis/farmacologia , Flavonóis/análise , Flavonóis/química , Folhas de Planta/químicaRESUMO
Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.
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Skin aging caused by various endogenous and exogenous factors results in structural and functional changes to skin components. However, the role of senescent cells in skin aging has not been clarified. To elucidate the function of senescent cells in skin aging, we evaluated the effects of the glutaminase inhibitor BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl)ethyl sulfide) on human senescent dermal fibroblasts and aged human skin. Here, primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, ionizing radiation, and treatment with doxorubicin, an anticancer drug. Cell viability of HDFs was assessed after BPTES treatment. A mouse/human chimeric model was created by subcutaneously transplanting whole skin grafts from aged humans into nude mice. The model was treated intraperitoneally with BPTES or vehicle for 30 days. Skin samples were collected and subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, and histological analysis. BPTES selectively eliminated senescent dermal fibroblasts regardless of the method used to induce senescence; aged human skin grafts treated with BPTES exhibited increased collagen density, increased cell proliferation in the dermis, and decreased aging-related secretory phenotypes, such as matrix metalloprotease and interleukin. These effects were maintained in the grafts 1 month after termination of the treatment. In conclusion, selective removal of senescent dermal fibroblasts can improve the skin aging phenotype, indicating that BPTES may be an effective novel therapeutic agent for skin aging.
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Glutaminase , Pele , Animais , Camundongos , Humanos , Idoso , Camundongos Nus , Fibroblastos/fisiologia , Células Cultivadas , Senescência Celular/fisiologiaRESUMO
INTRODUCTION: Kidney-type glutaminase (KGA) has been an important anti-tumor drug target, and KGA allosteric inhibitors attracted much interest for their superior enzymatic specificity with good drug safety profiles. For glutaminase allosteric inhibitors such as BPTES, CB-839 and Selen derivatives, the low solubility remains as the main factor that limits in vivo efficacy. The 1,3,4-Selenadiazole compound CPD 23 showed improved in vivo efficacy but worse solubility; however, the graft polymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCap-PVA-PEG), Soluplus® (SOL) stood out as an excellent delivery carrier for CPD 23. METHODS: The CPD 23@SOL micelles were prepared, optimized and evaluated through on the basis of solubility improvement and loading capacity. Characterizations of particle size and Zeta potential by dynamic light scattering, morphology by transmission electron microscopy and solid state by X-ray powder diffraction were closely conducted. The biological studies included the tumor cell growth inhibition, blood and liver microsomal stability, in vivo pharmacokinetics and tissue biodistribution. RESULTS: At 1:20 ratio of CPD 23:SOL, CPD 23@SOL micelles were well-dispersed, spherical and stable, with size less than 200 nm with encapsulation efficiency of more than 90%. This SOL micellar system significantly increased the aqueous solubility of CPD 23 by 15,000 folds. Particularly, CPD 23@SOL micelles demonstrated higher stability in blood and liver microsomes, showing approximately 86% remaining at 2 h incubation and about 66% at 4 h, respectively. In addition, with or without micellar formulation, CPD 23 maintained essentially the same inhibitory activity in tumor cells. Interestingly, CPD 23@SOL micelles significantly improved the pharmacokinetic exposure, prolonged the in vivo circulation and dramatically changed tissue biodistributions of CPD 23. CONCLUSION: The current work provided an encouraging and practical delivery system for novel Selenadiazoles and glutaminase allosteric inhibitors whose poor water-soluble characteristic has been a bottleneck for the field.
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Glutaminase , Micelas , Portadores de Fármacos , Polietilenoglicóis , Polímeros , Solubilidade , Distribuição TecidualRESUMO
Kabosu (Citrus sphaerocarpa Hort. ex Tanaka) fruits have pleasant and fresh odors and have been used as raw materials for vinegar, seasonings, jams, marmalades and juices in Japan. The n-butanol extracts from kabosu fruits were prepared and a component in the extract was purified by column chromatography and HPLC to afford compounds 1-3. Three compounds, 5-(hydroxymethyl)-2-furaldehyde (1), umbelliferone (2) and oxypeucedanin hydrate (3), have been isolated from kabosu, and the structures of compounds 1-3 were elucidated by 1 D and 2 D NMR as well as EI-MS. Compound 2 exhibited potent glutaminase inhibitory activity with an IC50 value of 1.33 mM. This is the first report on glutaminase inhibitory activity of 2 and the isolation of three compounds 1-3 from kabosu fruits.
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Citrus , Frutas , Glutaminase , Odorantes , Extratos Vegetais/farmacologia , UmbeliferonasRESUMO
Glutaminase is an important target that is often over expressed in neurodegenerative andãlifestyle related diseases but few effective inhibitors of this enzyme have yet reached clinical trials. Ursolic acid (1), betulinic acid (2) and oleanolic acid (3), three pentacyclic triterpene acids, have been isolated from the leaves of Thymus vulgaris L. Enzyme inhibition experiments demonstrated their inhibitory effects against glutaminase activity. Compound 2 significantly inhibited the glutaminase activity with IC50 of 0.31 mM, stronger than the positive control 6-diazo-5-oxo-L-norleucine (DON) with IC50 of 0.57 mM. Compound 2 may serve as a potential lead compound for the prevention and treatment of neurodegenerative diseases and lifestyle related diseases by targeting glutaminase. This is the first report on glutaminase inhibitory activities of 1-3 isolated from T. vulgaris L.
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Ácido Oleanólico , Thymus (Planta) , Triterpenos , Glutaminase , Ácido Oleanólico/farmacologia , Triterpenos Pentacíclicos/farmacologia , Folhas de Planta , Triterpenos/farmacologiaRESUMO
Glutaminase is an important target that is often over-expressed in neurodegenerative and lifestyle-related diseases but few effective inhibitors of this enzyme have yet reached clinical trials. Three compounds isolated from fresh leaves of Diospyros kaki Thunberg, ursolic acid (1), rotungenic acid (2) and barbinervic acid (3), were identified by analyzing their NMR and MS spectral data and comparison of these with reported data. The IC50 values of 1-3 and 6-diazo-5-oxo-L-norleucine (DON) as control were 775, 13, 14, and 434 µM, respectively. Compounds 2 and 3 showed higher glutaminase inhibitory activities than DON. Compounds 2 and 3 may serve as potential lead compounds for the prevention and treatment of neurodegenerative and lifestyle-related diseases by targeting glutaminase. This is the first report on glutaminase inhibitory activities of 2 and 3.
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Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.
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Adenocarcinoma de Células Claras , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , Adenocarcinoma de Células Claras/genética , Proteínas de Ligação a DNA/genética , Glutaminase/genética , Glutamina/metabolismo , Neoplasias Ovarianas/genética , Fatores de Proteção , Fatores de Transcrição/genéticaRESUMO
Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.
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Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.
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Isquemia Encefálica/patologia , Exossomos/metabolismo , Glutaminase/metabolismo , Inflamação/patologia , Microglia/imunologia , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/imunologia , Exossomos/imunologia , Inflamação/enzimologia , Inflamação/imunologia , Microglia/enzimologia , Ratos , Ratos Sprague-DawleyRESUMO
An important hallmark of cancer is 'metabolic reprogramming' or the rewiring of cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.
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Microglial activation is a key pathogenic process at the onset of Alzheimer's disease (AD). Identifying regulators of microglial activation bears great potential in elucidating causes and mechanisms of AD and determining candidates for early intervention. Previous studies demonstrate abnormal elevation of glutaminase C (GAC) in HIV-infected or immune-activated microglia. However, whether GAC elevation causes microglial activation remains unknown. In this study, we found heightened expression levels of GAC in early AD mouse brain tissues compared with those in control littermates. Investigations on an in vitro neuroinflammation model revealed that GAC is increased in primary mouse microglia following pro-inflammatory stimulation. To model GAC elevation we overexpressed GAC by plasmid transfection and observed that GAC-overexpression shift the microglial phenotype to a pro-inflammatory state. Treatment with BPTES, a glutaminase inhibitor, reversed LPS-induced microglial activation and inflammation. Furthermore, we discovered that GAC overexpression in mouse microglia increased exosome release and changed exosome content, which includes specific packaging of pro-inflammatory miRNAs that activate microglia. Together, our results demonstrate a causal effect of GAC elevation on microglial activation and exosome release, both of which promote the establishment of a pro-inflammatory microenvironment. Therefore, GAC may have important relevance to the pathogenesis of AD.
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We uncovered the neurotransmitter N-acetyl-aspartyl-glutamate (NAAG) as a reservoir providing glutamate to promote cancer growth, and demonstrated that inhibition of NAAG hydrolysis by targeting glutamate carboxypeptidase II is a viable strategy for cancer therapy. Our study also suggests that NAAG concentration in plasma could be a non-invasive measurement to monitor cancer progression.
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N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.