scholarly journals Sex Differences in Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities to Treatment

2021 ◽  
Author(s):  
Jasmin Sponagel ◽  
Jill K. Jones ◽  
Cheryl Frankfater ◽  
Shanshan Zhang ◽  
Olivia Tung ◽  
...  
Keyword(s):  
Amino Acids ◽  
Sex Differences ◽  
Pyruvate Carboxylase ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Normal Metabolism ◽  
Male Patients ◽  
Glutaminase 1 ◽  
Metabolite Abundance ◽  
Glutamine Uptake

Sex differences in normal metabolism are well described, but whether they persist in cancerous tissue is unknown. We assessed metabolite abundance in glioblastoma surgical specimens and found that male glioblastomas are enriched for amino acids, including glutamine. Using PET imaging, we found that gliomas in male patients exhibit significantly higher glutamine uptake. These sex differences were well-modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and TCA cycle replenishment. Females were resistant to GLS inhibition through greater pyruvate carboxylase-mediated TCA cycle replenishment. Thus, clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism is an opportunity to improve treatments for all patients through further laboratory and clinical research.

scholarly journals TAMI-37. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii221-ii221
Author(s):  
Jasmin Sponagel ◽  
Shanshan Zhang ◽  
Jill Jones ◽  
Prakash Chinnaiyan ◽  
Joshua Rubin ◽  
...  
Keyword(s):  
Amino Acids ◽  
Sex Differences ◽  
Amino Acid ◽  
Redox State ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Tca Cycle ◽  
Primary Brain Tumor ◽  
Male And Female ◽  
Amino Acid Requirements

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in male GBM. We further confirmed sex differences in redox state through pharmacological depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. Finally, we found that mitochondrial structure and function, including TCA cycle flux, NADH levels, and antioxidant activity, differ between male and female GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutamine to regulate ROS levels, and (3) sex differences in mitochondrial physiology may result in ROS accumulation and increased susceptibility to drugs targeting the redox state in male GBM. Our data reveal novel metabolic targets for GBM and underline the importance of considering sex in metabolic targeting approaches.

scholarly journals Pyruvate carboxylase and cancer progression

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Violet A. Kiesel ◽  
Madeline P. Sheeley ◽  
Michael F. Coleman ◽  
Eylem Kulkoyluoglu Cotul ◽  
Shawn S. Donkin ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Pyruvate Carboxylase ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Whole Body ◽  
Β Cells ◽  
Adverse Conditions ◽  
Metastatic Process

AbstractPyruvate carboxylase (PC) is a mitochondrial enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate (OAA), serving to replenish the tricarboxylic acid (TCA) cycle. In nonmalignant tissue, PC plays an essential role in controlling whole-body energetics through regulation of gluconeogenesis in the liver, synthesis of fatty acids in adipocytes, and insulin secretion in pancreatic β cells. In breast cancer, PC activity is linked to pulmonary metastasis, potentially by providing the ability to utilize glucose, fatty acids, and glutamine metabolism as needed under varying conditions as cells metastasize. PC enzymatic activity appears to be of particular importance in cancer cells that are unable to utilize glutamine for anaplerosis. Moreover, PC activity also plays a role in lipid metabolism and protection from oxidative stress in cancer cells. Thus, PC activity may be essential to link energy substrate utilization with cancer progression and to enable the metabolic flexibility necessary for cell resilience to changing and adverse conditions during the metastatic process.

scholarly journals Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

2015 ◽  
Vol 396 (8) ◽  
pp. 937-947
Author(s):  
Miriam R. Reynolds ◽  
Brian F. Clem
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Tca Cycle ◽  
Viable Cell ◽  
Cell Number ◽  
Glutamine Metabolism ◽  
Viable Cell Number ◽  
Tumor Cell Growth ◽  
Pparγ Agonist ◽  
Glutamine Uptake

Abstract Enhanced glutamine metabolism is required for tumor cell growth and survival, which suggests that agents targeting glutaminolysis may have utility within anti-cancer therapies. Troglitazone, a PPARγ agonist, exhibits significant anti-tumor activity and can alter glutamine metabolism in multiple cell types. Therefore, we examined whether troglitazone would disrupt glutamine metabolism in tumor cells and whether its action was reliant on PPARγ activity. We found that troglitazone treatment suppressed glutamine uptake and the expression of the glutamine transporter, ASCT2, and glutaminase. In addition, troglitazone reduced 13C-glutamine incorporation into the TCA cycle, decreased [ATP], and resulted in an increase in reactive oxygen species (ROS). Further, troglitazone treatment decreased tumor cell growth, which was partially rescued with the addition of the TCA-intermediate, α-ketoglutarate, or the antioxidant N-acetylcysteine. Importantly, troglitazone’s effects on glutamine uptake or viable cell number were found to be PPARγ-independent. In contrast, troglitazone caused a decrease in c-Myc levels, while the proteasomal inhibitor, MG132, rescued c-Myc, ASCT2 and GLS1 expression, as well as glutamine uptake and cell number. Lastly, combinatorial treatment of troglitazone and metformin resulted in a synergistic decrease in cell number. Therefore, characterizing new anti-tumor properties of previously approved FDA therapies supports the potential for repurposing of these agents.

scholarly journals UGCG influences glutamine metabolism of breast cancer cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nina Schömel ◽  
Sarah E. Hancock ◽  
Lisa Gruber ◽  
Ellen M. Olzomer ◽  
Frances L. Byrne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Key Enzyme ◽  
Cancer Types ◽  
Supply Environment ◽  
Glutamine Uptake

Abstract UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo. Increased UGCG synthesis is associated with pro-cancerous processes such as increased proliferation and multidrug resistance in several cancer types. We investigated the influence of UGCG overexpression on glutamine metabolism in breast cancer cells. We observed adapted glucose and glutamine uptake in a limited energy supply environment following UGCG overexpression. Glutamine is used for reinforced oxidative stress response shown by increased mRNA expression of glutamine metabolizing proteins such as glutathione-disulfide reductase (GSR) resulting in increased reduced glutathione (GSH) level. Augmented glutamine uptake is also used for fueling the tricarboxylic acid (TCA) cycle to maintain the proliferative advantage of UGCG overexpressing cells. Our data reveal a link between GSL and glutamine metabolism in breast cancer cells, which is to our knowledge a novel correlation in the field of sphingolipid research.

scholarly journals Glutamine Metabolism Is Essential for Human Cytomegalovirus Infection

2009 ◽  
Vol 84 (4) ◽  
pp. 1867-1873 ◽  
Author(s):  
Jeremy W. Chambers ◽  
Tobi G. Maguire ◽  
James C. Alwine
Keyword(s):  
Human Cytomegalovirus ◽  
Human Fibroblasts ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Glucose Starvation ◽  
Atp Production ◽  
The Tca Cycle ◽  
Infected Cells ◽  
Human Cytomegalovirus Infection ◽  
Glutamine Uptake

ABSTRACT Human fibroblasts infected with human cytomegalovirus (HCMV) were more viable than uninfected cells during glucose starvation, suggesting that an alternate carbon source was used. We have determined that infected cells require glutamine for ATP production, whereas uninfected cells do not. This suggested that during infection, glutamine is used to fill the tricarboxylic acid (TCA) cycle (anaplerosis). In agreement with this, levels of glutamine uptake and ammonia production increased in infected cells, as did the activities of glutaminase and glutamate dehydrogenase, the enzymes needed to convert glutamine to α-ketoglutarate to enter the TCA cycle. Infected cells starved for glutamine beginning 24 h postinfection failed to produce infectious virions. Both ATP and viral production could be rescued in glutamine-starved cells by the TCA intermediates α-ketoglutarate, oxaloacetate, and pyruvate, confirming that in infected cells, a program allowing glutamine to be used anaplerotically is induced. Thus, HCMV infection activates the mechanisms needed to switch the anaplerotic substrate from glucose to glutamine to accommodate the biosynthetic and energetic needs of the viral infection and to allow glucose to be used biosynthetically.

scholarly journals TBIO-01. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii467-iii467
Author(s):  
Jasmin Sponagel ◽  
Shanshan Zhang ◽  
Prakash Chinnaiyan ◽  
Joshua Rubin ◽  
Joseph Ippolito
Keyword(s):  
Sex Differences ◽  
Amino Acid ◽  
Redox State ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Crucial Component ◽  
Acid Metabolites ◽  
Novel Treatment Strategies ◽  
Glutaminase 1 ◽  
Metabolite Abundance

Abstract Glioblastoma (GBM) is an aggressive brain tumor in children and adults. It occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that males exhibit a significantly higher abundance of amino acid metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Furthermore, we found that male GBM cell cultures are significantly more sensitive to amino acid deprivation, which was almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells exhibited higher levels of GLS1, suggesting they are more dependent on glutamate. Indeed, we found that male GBM cells are more sensitive to pharmacological GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in males compared to females. We further confirmed sex differences in redox state through pharmacological depletion of glutathione that resulted in a significant increase in ROS and cell death in male GBM. Together, these data indicate that male GBM cells are more dependent on glutamine to regulate ROS levels. This reveals novel sex-specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

Synthesis and Breakdown of the Universal Precursors to Biological Metabolism Promoted by Ferrous Iron

2018 ◽  
Author(s):  
Kamila B. Muchowska ◽  
Sreejith Jayasree VARMA ◽  
Joseph Moran
Keyword(s):  
Amino Acids ◽  
Chemical Reaction ◽  
Metabolic Pathways ◽  
Ferrous Iron ◽  
Reaction Network ◽  
Tca Cycle ◽  
Chemical Reaction Network ◽  
Metabolic Precursors ◽  
Tca Cycle Intermediates

How core biological metabolism initiated and why it uses the intermediates, reactions and pathways that it does remains unclear. Life builds its molecules from CO<sub>2 </sub>and breaks them down to CO<sub>2 </sub>again through the intermediacy of just five metabolites that act as the hubs of biochemistry. Here, we describe a purely chemical reaction network promoted by Fe<sup>2+ </sup>in which aqueous pyruvate and glyoxylate, two products of abiotic CO<sub>2 </sub>reduction, build up nine of the eleven TCA cycle intermediates, including all five universal metabolic precursors. The intermediates simultaneously break down to CO<sub>2 </sub>in a life-like regime resembling biological anabolism and catabolism. Introduction of hydroxylamine and Fe<sup>0 </sup>produces four biological amino acids. The network significantly overlaps the TCA/rTCA and glyoxylate cycles and may represent a prebiotic precursor to these core metabolic pathways.

scholarly journals Profiles of Secondary Metabolites (Phenolic Acids, Carotenoids, Anthocyanins, and Galantamine) and Primary Metabolites (Carbohydrates, Amino Acids, and Organic Acids) during Flower Development in Lycoris radiata

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 248
Author(s):  
Chang Ha Park ◽  
Hyeon Ji Yeo ◽  
Ye Jin Kim ◽  
Bao Van Nguyen ◽  
Ye Eun Park ◽  
...  
Keyword(s):  
Amino Acids ◽  
Secondary Metabolites ◽  
Organic Acids ◽  
Phenolic Acids ◽  
Flower Development ◽  
Developmental Stages ◽  
Tca Cycle ◽  
Primary And Secondary Metabolites ◽  
Hydrophilic Compounds ◽  
Tca Cycle Intermediates

This study aimed to elucidate the variations in primary and secondary metabolites during Lycorisradiata flower development using high performance liquid chromatography (HPLC) and gas chromatography time-of-flight mass spectrometry (GC-TOFMS). The result showed that seven carotenoids, seven phenolic acids, three anthocyanins, and galantamine were identified in the L. radiata flowers. Most secondary metabolite levels gradually decreased according to the flower developmental stages. A total of 51 metabolites, including amines, sugars, sugar intermediates, sugar alcohols, amino acids, organic acids, phenolic acids, and tricarboxylic acid (TCA) cycle intermediates, were identified and quantified using GC-TOFMS. Among the hydrophilic compounds, most amino acids increased during flower development; in contrast, TCA cycle intermediates and sugars decreased. In particular, glutamine, asparagine, glutamic acid, and aspartic acid, which represent the main inter- and intracellular nitrogen carriers, were positively correlated with the other amino acids and were negatively correlated with the TCA cycle intermediates. Furthermore, quantitation data of the 51 hydrophilic compounds were subjected to partial least-squares discriminant analyses (PLS-DA) to assess significant differences in the metabolites of L. radiata flowers from stages 1 to 4. Therefore, this study will serve as the foundation for a biochemical approach to understand both primary and secondary metabolism in L. radiata flower development.

scholarly journals Sex-Specific Differences in Glioblastoma

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1783
Author(s):  
Anna Carrano ◽  
Juan Jose Juarez ◽  
Diego Incontri ◽  
Antonio Ibarra ◽  
Hugo Guerrero Cazares
Keyword(s):  
Sex Differences ◽  
Immune System ◽  
Molecular Level ◽  
Deep Understanding ◽  
Protective Role ◽  
Men And Women ◽  
Individualized Approach ◽  
Male Patients ◽  
Outcome Differences

Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.

Lobetyolin inhibits the proliferation of breast cancer cells via ASCT2 down-regulation-induced apoptosis

2021 ◽  
pp. 096032712110214
Author(s):  
Yansong Chen ◽  
Ye Tian ◽  
Gongsheng Jin ◽  
Zhen Cui ◽  
Wei Guo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Glutamine Metabolism ◽  
Down Regulation ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Glutamine Uptake

This study aimed to investigate the anti-cancer effect of lobetyolin on breast cancer cells. Lobetyolin was incubated with MDA-MB-231 and MDA-MB-468 breast cancer cells for 24 h. Glucose uptake and the mRNA expression of GLUT4 ( SLC2A4), HK2 and PKM2 were detected to assess the effect of lobetyolin on glucose metabolism. Glutamine uptake and the mRNA expression of ASCT2 ( SLC1A5), GLS1, GDH and GLUL were measured to assess the effect of lobetyolin on glutamine metabolism. Annexin V/PI double staining and Hoechst 33342 staining were used to investigate the effect of lobetyolin on cell apoptosis. Immunoblot was employed to estimate the effect of lobetyolin on the expression of proliferation-related markers and apoptosis-related markers. SLC1A5 knockdown with specific siRNA was performed to study the role of ASCT2 played in the anti-cancer effect of lobetyolin on MDA-MB-231 and MDA-MB-468 breast cancer cells. C-MYC knockdown with specific siRNA was performed to study the role of c-Myc played in lobetyolin-induced ASCT2 down-regulation. Myr-AKT overexpression was performed to investigate the role of AKT/GSK3β signaling played in lobetyolin-induced down-regulation of c-Myc and ASCT2. The results showed that lobetyolin inhibited the proliferation of both MDA-MB-231 and MDA-MB-468 breast cancer cells. Lobetyolin disrupted glutamine uptake via down-regulating ASCT2. SLC1A5 knockdown attenuated the anti-cancer effect of lobetyolin. C-MYC knockdown attenuated lobetyolin-caused down-regulation of ASCT2 and Myr-AKT overexpression reversed lobetyolin-caused down-regulation of both c-Myc and ASCT2. In conclusion, the present work suggested that lobetyolin exerted anti-cancer effect via ASCT2 down-regulation-induced apoptosis in breast cancer cells.

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