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1.
Sci Rep ; 13(1): 149, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599897

RESUMO

Oncocytic thyroid cancer is characterized by the aberrant accumulation of abnormal mitochondria in the cytoplasm and a defect in oxidative phosphorylation. We performed metabolomics analysis to compare metabolic reprogramming among the oncocytic and non-oncocytic thyroid cancer cell lines XTC.UC1 and TPC1, respectively, and a normal thyroid cell line Nthy-ori 3-1. We found that although XTC.UC1 cells exhibit higher glucose uptake than TPC1 cells, the glycolytic intermediates are not only utilized to generate end-products of glycolysis, but also diverted to branching pathways such as lipid metabolism and the serine synthesis pathway. Glutamine is preferentially used to produce glutathione to reduce oxidative stress in XTC.UC1 cells, rather than to generate α-ketoglutarate for anaplerotic flux into the TCA cycle. Thus, growth, survival and redox homeostasis of XTC.UC1 cells rely more on both glucose and glutamine than do TPC1 cells. Furthermore, XTC.UC1 cells contained higher amounts of intracellular amino acids which is due to higher expression of the amino acid transporter ASCT2 and enhanced autophagy, thus providing the building blocks for macromolecules and energy production. These metabolic alterations are required for oncocytic cancer cells to compensate their defective mitochondrial function and to alleviate excess oxidative stress.


Assuntos
Glutamina , Neoplasias da Glândula Tireoide , Humanos , Linhagem Celular Tumoral , Glutamina/metabolismo , Glicólise , Metabolômica/métodos , Mitocôndrias/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
2.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674708

RESUMO

Periods of low energy supply are challenging conditions for organisms and cells during fasting or famine. Although changes in nutrient levels in the blood are first sensed by endothelial cells, studies on their metabolic adaptations to diminished energy supply are lacking. We analyzed the dynamic metabolic activity of human umbilical vein endothelial cells (HUVECs) in basal conditions and after serum starvation. Metabolites of glycolysis, the tricarboxylic acid (TCA) cycle, and the glycerol pathway showed lower levels after serum starvation, whereas amino acids had increased levels. A metabolic flux analysis with 13C-glucose or 13C-glutamine labeling for different time points reached a plateau phase of incorporation after 30 h for 13C-glucose and after 8 h for 13C-glutamine under both experimental conditions. Notably, we observed a faster label incorporation for both 13C-glucose and 13C-glutamine after serum starvation. In the linear range of label incorporation after 3 h, we found a significantly faster incorporation of central carbon metabolites after serum starvation compared to the basal state. These findings may indicate that endothelial cells develop increased metabolic activity to cope with energy deficiency. Physiologically, it can be a prerequisite for endothelial cells to form new blood vessels under unfavorable conditions during the process of angiogenesis in vivo.


Assuntos
Glutamina , Inanição , Humanos , Glutamina/metabolismo , Aminoácidos/metabolismo , Glicólise , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo
3.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675195

RESUMO

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study's purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m2) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m2) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment.


Assuntos
Glutamina , Gordura Intra-Abdominal , Humanos , Glutamina/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Metabolismo Energético , Piruvatos/metabolismo , Tecido Adiposo/metabolismo
4.
Nutrients ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615909

RESUMO

We aimed to assess the lipopolysaccharide (LPS), or heat shock (HS) induction, and glutamine-modulating effects on heat shock protein-90α (HSP90α) and cytokines in an ex vivo model using peripheral blood mononuclear cells (PBMCs). The PBMCs of patients with septic shock, trauma-related systemic inflammatory response syndrome (SIRS), and healthy subjects were incubated with 1 µg/mL LPS at 43 °C (HS). Glutamine 10 mM was added 1 hour before or after induction or not at all. We measured mRNA HSP90α, monocyte (m) and lymphocyte (l) HSP90α proteins, interleukin (IL)-1b, -6, -8, -10, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) supernatant levels. Heat shock increased the HSP90α mRNA and mHSP90α in all groups (10-fold in sepsis, p < 0.001 and p = 0.047, respectively). LPS induced the mHSP90α and lHSP90α in healthy (p < 0.001) and mHSP90α in SIRS (p = 0.004) but not in sepsis. LPS induced the cytokines at 24 and 48 h in all groups, especially in trauma (p < 0.001); HS only induced the IL-8 in healthy (p = 0.003) and septic subjects (p = 0.05). Glutamine at 10 mM before or after stimulation did not alter any induction effect of LPS or HS on HSP90α mRNA and mHSP90α protein in sepsis. In SIRS, glutamine before LPS decreased the mHSP90α but increased it when given after HS (p = 0.018). Before or after LPS (p = 0.049) and before HS (p = 0.018), glutamine decreased the lHSP90α expression in sepsis but increased it in SIRS when given after HS (p = 0.003). Regarding cytokines, glutamine enhanced the LPS-induced MCP-1 at 48 h in healthy (p = 0.011), SIRS (p < 0.001), and sepsis (p = 0.006). In conclusion, glutamine at 10 mM, before or after LPS and HS, modulates mHSP90α and lHSP90α in sepsis and SIRS differently and unpredictably. Although it does not alter the stimulation effect on interleukins, glutamine enhances the LPS induction effect on supernatant MCP-1 in all groups. Future research should seek to elucidate better the impact of glutamine and temperature modulation on HSP90α and MCP-1 pathways in sepsis and trauma.


Assuntos
Leucócitos Mononucleares , Sepse , Humanos , Leucócitos Mononucleares/metabolismo , Glutamina/farmacologia , Glutamina/metabolismo , Lipopolissacarídeos/farmacologia , Sepse/metabolismo , Síndrome de Resposta Inflamatória Sistêmica , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucinas/metabolismo , Proteínas de Choque Térmico/metabolismo , RNA Mensageiro/metabolismo
5.
Sci Adv ; 9(1): eabo7555, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598999

RESUMO

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.


Assuntos
Glutamina , Folículo Piloso , Animais , Humanos , Camundongos , Glutamina/metabolismo , Queratinócitos , Regeneração , Pele/metabolismo , Cicatrização , Microbiota
6.
Biol Direct ; 18(1): 1, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631876

RESUMO

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy that requires effective novel therapies. M2 macrophages are abundant in the PC microenvironment and promote cancer progression. Exosomes are emerging mediators of the crosstalk between cancer cells and the microenvironment. This study was conducted to explore the role of M2 macrophage-derived exosomes in PC. METHODS: Exosomes derived from M2 macrophages were extracted. miR-193b-3p and TRIM62 were overexpressed or silenced to examine their function in PC. Luminescence assays were used to investigate the interaction between miR-193b-3p and TRIM62. Cell proliferation was examined by EdU staining. Would healing and transwell assays were applied to evaluate cell migration and invasion. Co-immunoprecipitation was used to assess the interaction between TRIM62 and c-Myc. Gene and protein expressions were analyzed by quantitative RT-PCR and immunoblotting, respectively. RESULTS: M2 macrophage-derived exosomal miR-193b-3p promoted the proliferation, migration, invasion, and glutamine uptake of SW1990 cells. Mechanism study revealed that TRIM62 is a target of miR-193b-3p. TRIM62 inhibited the proliferation, migration, invasion, and glutamine uptake of SW1990 cells by promoting c-Myc ubiquitination. Our data also suggested that TRIM62 expression negatively correlated with miR-193b-3p and c-Myc expression. High-expression of miR-193b-3p and c-Myc predicts poor prognosis, whereas low-expression of TRIM62 predicts poor prognosis in patients with PC. CONCLUSION: M2 macrophage-derived exosomal miR-193b-3p enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, resulting in the decrease of c-Myc ubiquitination. This study not only reveals the mechanism underlying the crosstalk between M2 macrophages and PC cells but also suggests a promising therapeutic target for PC.


Assuntos
Exossomos , MicroRNAs , Neoplasias Pancreáticas , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Glutamina/metabolismo , Neoplasias Pancreáticas/genética , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Proliferação de Células , Macrófagos/metabolismo , Microambiente Tumoral
7.
Cancer Lett ; 555: 216040, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36565920

RESUMO

Pancreatic stellate cells (PSCs) are crucial for metabolism and disease progression in pancreatic ductal adenocarcinoma (PDAC). However, detailed mechanisms of PSCs in glutamine (Gln) metabolism and tumor-stromal metabolic interactions have not been well clarified. Here we showed that tumor tissues displayed Gln deficiency in orthotopic PDAC models. Single-cell RNA sequencing analysis revealed metabolic heterogeneity in PDAC, with significantly higher expression of Gln catabolism pathway in stromal cells. Significantly higher glutamine synthetase (GS) protein expression was further validated in human tissues and cells. Elevated GS levels in tumor and stroma were independently prognostic of poorer prognosis in PDAC patients. Gln secreted by PSCs increased basal oxygen consumption rate in PCCs. Depletion of GS in PSCs significantly decreased PCCs proliferation in vitro and in vivo. Mechanistically, activation of Wnt signaling induced directly binding of ß-catenin/TCF7 complex to GS promoter region and upregulated GS expression. Rescue experiments testified that GS overexpression recovered ß-catenin knockdown-mediated function on Gln synthesis and tumor-promoting ability of PSCs. Overall, these findings identify the Wnt/ß-catenin/TCF7/GS-mediated growth-promoting effect of PSCs and provide new insights into stromal Gln metabolism, which may offer novel therapeutic strategies for PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Glutamina/metabolismo , Células Estreladas do Pâncreas/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fator 1 de Transcrição de Linfócitos T/metabolismo
8.
Redox Biol ; 59: 102581, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565645

RESUMO

Mucus forms the first line of defence of the intestinal mucosa barrier, and mucin is its core component. Glutamine is a vital energy substance for goblet cells; it can promote mucus synthesis and alleviate damage to the intestinal mucus barrier after burn injury, but its mechanism is not fully understood. This study focused on the molecular mechanisms underlying the effects of glutamine on the synthesis and modification of mucin 2 (MUC2) by using animal and cellular models of burn sepsis. We found that anterior gradient-2 (AGR2) plays a key role in the posttranslational modification of MUC2. Oxidative stress induced by burn sepsis enhanced the S-glutathionylation of AGR2, interfered with the processing and modification of MUC2 precursors by AGR2 and blocked the synthesis of mature MUC2. Further studies revealed that NADPH, catalysed by glucose-6-phosphate dehydrogenase (G6PD), is a key molecule in inhibiting oxidative stress and regulating AGR2 activity. Glutamine promotes O-linked N-acetylglucosamine (O-GlcNAc) modification of G6PD via the hexosamine pathway, which facilitates G6PD homodimer formation and increases NADPH synthesis, thereby inhibiting AGR2 S-glutathionylation and promoting MUC2 maturation, ultimately reducing damage to the intestinal mucus barrier after burn sepsis. Overall, we have demonstrated that the central mechanisms of glutamine in promoting MUC2 maturation and maintaining the intestinal mucus barrier are the enhancement of G6PD glycosylation and inhibition of AGR2 S-glutathionylation.


Assuntos
Glucosefosfato Desidrogenase , Glutamina , Animais , Camundongos , Glucosefosfato Desidrogenase/metabolismo , Glutamina/metabolismo , Células Caliciformes/metabolismo , Muco/metabolismo , NADP/metabolismo
9.
Eur J Med Chem ; 246: 115014, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36525694

RESUMO

Tumor cells often exhibit metabolic reprogramming to maintain their rapid growth and proliferation. Glutaminase 1 (GLS1) has been viewed as a promising target in the glutamine metabolism pathway for the treatment of malignant tumors. Using structure-based drug design approaches, a novel series of GLS1 allosteric inhibitors were designed and synthesized. Compound 41a (LWG-301) with an alkane chain "tail" group had potent biochemical and cellular GLS1 activity, and improved metabolic stability. LWG-301 exhibited moderate antitumor effects in HCT116 xenograft model, with TGI of 38.9% in vivo. Mechanistically, LWG-301 could significantly block glutamine metabolism, resulting in changes in the corresponding amino acid levels in cells, induce a concentration-dependent increase in intracellular ROS levels, and induce apoptosis. Taken together, this paper provides more structural references and new design strategy for the development of GLS1 allosteric inhibitors.


Assuntos
Glutaminase , Glutamina , Humanos , Proliferação de Células , Glutamina/metabolismo , Xenoenxertos
10.
Eur J Pharmacol ; 940: 175323, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36535492

RESUMO

Glutamine, as the most abundant amino acid in the body, participates in the biological synthesis of nucleotides and other non-essential amino acids in the process of cell metabolism. Recent studies showed that glutamine metabolic reprogramming is an important signal during cancer development and progression. This metabolic signature in cancer cells can promote the development of cancer by activating multiple signaling pathways and oncogenes. It can also be involved in tumor immune regulation and promote the development of drug resistance to tumors. In this review, we mainly summarize the role of glutamine metabolic reprogramming in tumors, including the regulation of multiple signaling pathways. We further discussed the promising tumor treatment strategy by targeting glutamine metabolism alone or in combination with chemotherapeutics.


Assuntos
Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Neoplasias/patologia , Transformação Celular Neoplásica/metabolismo , Aminoácidos , Resistência a Múltiplos Medicamentos
11.
Eur J Pharmacol ; 940: 175480, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36566008

RESUMO

Intestinal intraepithelial lymphocytes (IELs) play a sentinel role in the mucosal immune system because of their unique anatomical location in the epithelial layer. The disruption of IEL homeostasis is implicated in driving the intestinal injury of many typical inflammatory disorders, such as inflammatory bowel disease (IBD) and sepsis. Therefore, it is meaningful to alleviate intestinal injury by restoring IEL homeostasis in disease conditions. This study explores the effects of glutamine on intestinal IEL homeostasis in a murine model of burn sepsis. We report that glutamine inhibits inflammatory response and reduces injury in the small intestine of burn septic mice. This effect is attributed to the maintaining of IEL homeostasis by suppressing apoptosis and restoring the disrupted subpopulation balance induced by burn sepsis. Mechanistically, we show that glutamine does not affect the IL-15 dependent mechanisms that drive the maintenance and differentiation of IELs. Instead, glutamine sustains IEL homeostasis by upregulate aryl hydrocarbon receptor (AHR) and interleukin (IL)-22 transcription and expression. Consistently, the protective roles of glutamine in burn septic mice were repressed by further supplement with an AHR antagonist CH-223191. Collectively, our study reveals a new role of glutamine to maintain IEL homeostasis by activating the AHR signaling pathway, which in turn ameliorates intestinal injury in burn sepsis.


Assuntos
Queimaduras , Linfócitos Intraepiteliais , Sepse , Camundongos , Animais , Glutamina/farmacologia , Glutamina/metabolismo , Mucosa Intestinal , Homeostase , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Queimaduras/complicações , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Camundongos Endogâmicos C57BL
12.
Life Sci ; 314: 121327, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36584912

RESUMO

AIMS: This study investigated whether l-glutamine (Gln) and/or l-leucine (Leu) administration could attenuate muscle atrophy in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. MATERIALS AND METHODS: Septic mice were given a daily intraperitoneal injection of Gln, Leu, or Gln plus Leu, and mice were sacrificed on either day 1 or 4 after CLP. Blood and muscles were collected for analysis of amino acid contents and markers related to protein degradation, muscle regeneration, and protein synthesis. KEY FINDINGS: Leu treatment alone increased both muscle mass and total muscle protein content on day 4 after CLP. Gln administration reduced muscular Gln contents on day 1 and enhanced plasma Gln levels on day 4. Higher plasma branched-chain amino acid (BCAA) abundances and lower muscular BCAA levels were observed in Leu-treated mice on day 4. Gln and Leu individually suppressed muscle expressions of the E3 ubiquitin ligase genes, Trim63 and Fbxo32, on day 4 after CLP. As to muscle expressions of myogenic genes, both Gln and Leu upregulated Myog expression on day 1, but Leu alone enhanced Myf5 gene expression, whereas Gln plus Leu increased MyoD and Myog expression levels on day 4. Akt/mammalian target of rapamycin (mTOR) signaling was only activated by Gln and Leu when individually administered. SIGNIFICANCE: Gln and/or Leu administration reduces sepsis-induced muscle degradation and promotes myogenic gene expressions. Leu treatment alone had more-pronounced effects on maintaining muscle mass during sepsis. A combination of Gln and Leu failed to show synergistic effects on alleviating sepsis-induced muscle atrophy.


Assuntos
Glutamina , Sepse , Camundongos , Animais , Glutamina/farmacologia , Glutamina/metabolismo , Leucina/farmacologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Aminoácidos de Cadeia Ramificada/metabolismo , Músculo Esquelético/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Mamíferos/metabolismo
13.
Biochim Biophys Acta Biomembr ; 1865(2): 184098, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36481181

RESUMO

Apolipoprotein A-I (apoA-I) is the main protein of high-density lipoprotein and is comprised of a helical bundle domain and a C-terminal (CT) domain encompassing the last ~65 amino acid residues of the 243-residue protein. The CT domain contains three putative helices (helix 8, 9, and 10) and is critical for initiating lipid binding and harbors sites that mediate self-association of the lipid-free protein. Three lysine residues reside in helix-8 (K195, 206, 208), and three in helix-10 (K226, 238, 239). To determine the role of each CT lysine residue in apoA-I self-association, single, double and triple lysine to glutamine mutants were engineered via site-directed mutagenesis. Circular dichroism and chemical denaturation analysis revealed all mutants retained their structural integrity. Chemical crosslinking and size-exclusion chromatography showed a small effect on self-association when helix-8 lysine residues were changed into glutamine. In contrast, mutation of the three helix-10 lysine residues resulted in a predominantly monomeric protein and K226 was identified as a critical residue. When helix-10 glutamate residues 223, 234, or 235 were substituted with glutamine, reduced self-association was observed similar to that of the helix-10 lysine variants, suggesting ionic interactions between these residues. Thus, helix-10 is a critical part of apoA-I mediating self-association, and disruption of ionic interactions changes apoA-I from an oligomeric state into a monomer. Since the helix-10 triple mutant solubilized phospholipid vesicles at higher rates compared to wild-type apoA-I, this indicates monomeric apoA-I is more potent in lipid binding, presumably because helix-10 is fully accessible to interact with lipids.


Assuntos
Apolipoproteína A-I , Lisina , Apolipoproteína A-I/genética , Apolipoproteína A-I/química , Ligação Proteica , Lisina/genética , Lisina/metabolismo , Glutamina/metabolismo , Dicroísmo Circular
14.
Toxins (Basel) ; 14(12)2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-36548719

RESUMO

The basic biological function of glutamine synthetase (Gs) is to catalyze the conversion of ammonium and glutamate to glutamine. This synthetase also performs other biological functions. However, the roles of Gs in fungi, especially in filamentous fungi, are not fully understood. Here, we found that conditional disruption of glutamine synthetase (AflGsA) gene expression in Aspergillus flavus by using a xylose promoter leads to a complete glutamine deficiency. Supplementation of glutamine could restore the nutritional deficiency caused by AflGsA expression deficiency. Additionally, by using the xylose promoter for the downregulation of AflgsA expression, we found that AflGsA regulates spore and sclerotic development by regulating the transcriptional levels of sporulation genes abaA and brlA and the sclerotic generation genes nsdC and nsdD, respectively. In addition, AflGsA was found to maintain the balance of reactive oxygen species (ROS) and to aid in resisting oxidative stress. AflGsA is also involved in the regulation of light signals through the production of glutamine. The results also showed that the recombinant AflGsA had glutamine synthetase activity in vitro and required the assistance of metal ions. The inhibitor molecule L-α-aminoadipic acid suppressed the activity of rAflGsA in vitro and disrupted the morphogenesis of spores, sclerotia, and colonies in A. flavus. These results provide a mechanistic link between nutrition metabolism and glutamine synthetase in A. flavus and suggest a strategy for the prevention of fungal infection.


Assuntos
Aflatoxinas , Aspergillus flavus , Aspergillus flavus/metabolismo , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Glutamina/metabolismo , Xilose/metabolismo , Proteínas Fúngicas/metabolismo , Esporos Fúngicos , Estresse Oxidativo , Regulação Fúngica da Expressão Gênica
15.
Sci Adv ; 8(50): eabp8293, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525494

RESUMO

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Camundongos , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Glutaminase/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Glutamina/metabolismo , Isocitrato Desidrogenase
16.
Cells ; 11(23)2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36497182

RESUMO

Glutamine metabolism is critical both for the proliferation of cancer cells and the activation of CD8T cells to kill cancer cells. We aim to explore the relationship between the glutamine metabolism of CD8T cells and cancer cells and tumor immunity in the tumor microenvironment. In a TCGA cohort, we found that patients with high scores of glutamine-metabolism-related genes showed poor prognoses, and that a high score of glutamine-metabolism-related genes was an independent risk factor for HCC patients. In single-cell RNA-seq data, we found that, in some patients, the glutamine metabolism gene scores of tumor cells were significantly higher than those of CD8T cells, while decreased ratios of CD8-Tef-GZMA and suppressed tumor-killing activity of CD8-Tef-APOC2 were observed. A further genetic dynamics pseudotime analysis suggested that immune remodeling of these two subpopulations was accompanied by metabolic reprogramming. CD8-Tef-APOC2 in the dominant group tended to metabolize exogenous lipids, while the metabolic program of CD8-Tef-GZMA in the nondominant group was characterized by amino acid and endogenous lipid synthesis. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the proliferation of CD8T cells and improved the efficacy of PD-1 blockers. We proposed a new tool to quantify the glutamine partitioning between tumor cells and CD8T cells, through which the unique immune microenvironment could be identified at the transcriptome level. Furthermore, the simultaneous destruction of the glutamine metabolism in tumor cells and CD8T cells facilitated the enrichment of tumor-infiltrating CD8T cells and enhanced the efficacy of immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Glutamina/metabolismo , Neoplasias Hepáticas/patologia , Linfócitos T CD8-Positivos , Microambiente Tumoral
17.
Int J Mol Sci ; 23(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36499136

RESUMO

Metabolic alterations that support the supply of biosynthetic molecules necessary for rapid and sustained proliferation are characteristic of cancer. Some cancer cells rely on glutamine to maintain their energy requirements for growth. Glutamine is an important metabolite in cells because it not only links to the tricarboxylic acid cycle by producing α-ketoglutarate by glutaminase and glutamate dehydrogenase but also supplies other non-essential amino acids, fatty acids, and components of nucleotide synthesis. Altered glutamine metabolism is associated with cancer cell survival, proliferation, metastasis, and aggression. Furthermore, altered glutamine metabolism is known to be involved in therapeutic resistance. In recent studies, lncRNAs were shown to act on amino acid transporters and glutamine-metabolic enzymes, resulting in the regulation of glutamine metabolism. The lncRNAs involved in the expression of the transporters include the abhydrolase domain containing 11 antisense RNA 1, LINC00857, plasmacytoma variant translocation 1, Myc-induced long non-coding RNA, and opa interacting protein 5 antisense RNA 1, all of which play oncogenic roles. When it comes to the regulation of glutamine-metabolic enzymes, several lncRNAs, including nuclear paraspeckle assembly transcript 1, XLOC_006390, urothelial cancer associated 1, and thymopoietin antisense RNA 1, show oncogenic activities, and others such as antisense lncRNA of glutaminase, lincRNA-p21, and ataxin 8 opposite strand serve as tumor suppressors. In addition, glutamine-dependent cancer cells with lncRNA dysregulation promote cell survival, proliferation, and metastasis by increasing chemo- and radio-resistance. Therefore, understanding the roles of lncRNAs in glutamine metabolism will be helpful for the establishment of therapeutic strategies for glutamine-dependent cancer patients.


Assuntos
RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Glutamina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , RNA Antissenso
18.
Int J Mol Sci ; 23(23)2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36499623

RESUMO

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.


Assuntos
Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Glutaminase/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Ácido Glutâmico , Glucose/metabolismo
19.
Sci Adv ; 8(46): eabq5925, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36383674

RESUMO

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.


Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Diazo-Oxo-Norleucina/farmacologia , Diazo-Oxo-Norleucina/uso terapêutico , Glutamina/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico
20.
BMC Med ; 20(1): 440, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369023

RESUMO

BACKGROUND: Untreated celiac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated celiac disease. METHODS: Quantitative polymerase chain reaction (qPCR) was used to quantify the expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes (GUSB, IPO8, and YWHAZ) in duodenal biopsies collected from 84 children with untreated celiac disease and 58 disease controls. RESULTS: Significantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1, and SLC6A19. No significant difference in the expression was observed for G6PC3 or GOT1. CONCLUSIONS: Children with untreated celiac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients.


Assuntos
Doença Celíaca , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Doença Celíaca/genética , Gluconeogênese/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Glutamina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia
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