bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2020‒12‒13
sixteen papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Mol Omics. 2020 Dec 09.
      Triple-negative breast cancer (TNBC) is well-known for its metastatic aggressiveness and poor survival prognosis, accounting for nearly a quarter of cases in breast cancer. We performed intra- and extra-cellular profiling of 40 amino acids and derivatives on three cell lines and their culture media, including TNBC, non-TNBC and normal breast epithelial cells, using HILIC-MS/MS. Characteristic metabolic alteration of amino acids and derivatives was observed in TNBC cells, compared to non-TNBC cells, especially in correlated intra- and extra-cellular metabolic pathways. Intra-cellularly, quantified glutamic acid, β-alanine, aspartic acid, glutathione, N-acetyl-serine and N-acetyl-methionine were most significantly increased (>2-fold, p < 0.01 and VIP > 1) in TNBC cells. Extra-cellularly, significantly increased uptake of glutamine, serine, β-alanine, and lysine and elevated excretion of glutamic acid and l-cysteine-glutathione (p < 0.01 and VIP > 1) were observed by TNBC cells from or to their cell culture media. This study depicted a novel dynamic portrayal of metabolic dysregulation between TNBC and non-TNBC cells, correlated in both intra- and extra-cellular amino acid profiles. Quantification of these distinctive metabolites of TNBC cells might offer advanced understanding and new treatment targets for TNBC.
  2. Elife. 2020 Dec 08. pii: e62307. [Epub ahead of print]9
      An inadequate supply of amino acids leads to accumulation of uncharged tRNAs, which can bind and activate GCN2 kinase to reduce translation. Here, we show that glutamine-specific tRNAs selectively become uncharged when extracellular amino acid availability is compromised. In contrast, all other tRNAs retain charging of their cognate amino acids in a manner that is dependent upon intact lysosomal function. In addition to GCN2 activation and reduced total translation, the reduced charging of tRNAGln in amino acid-deprived cells also leads to specific depletion of proteins containing polyglutamine tracts including core binding factor α1, mediator subunit 12, transcriptional coactivator CBP and TATA-box binding protein. Treating amino acid-deprived cells with exogenous glutamine or glutaminase inhibitors restores tRNAGln charging and the levels of polyglutamine-containing proteins. Together, these results demonstrate that the activation of GCN2 and the translation of polyglutamine-encoding transcripts serve as key sensors of glutamine availability in mammalian cells.
    Keywords:  cell biology; human; mouse
  3. Cells. 2020 Dec 04. pii: E2598. [Epub ahead of print]9(12):
      Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.
    Keywords:  cancer; chemoresistance; hypoxia; metabolic reprogramming
  4. Cell Mol Biol (Noisy-le-grand). 2020 Oct 31. 66(7): 18-23
      This study was performed to research circB3GNTL1 control, miR-598 and its mechanism for cell proliferation, apoptosis and glutamine breakdown. For this purpose, CirB3GNTL1 and miR-598 expressions were detected by qRT-PCR in gastric and cell lines; MTT tests were performed to detect proliferation; flow cytometry was established in flow; glutamine decomposition was evaluated with glutamine, glutamic acid and α-keto-glutaric acid (α-KG) expression; Bcl-2, PCNA, ASCT2 and GLS1 expression levels were calculated; Methods of expression were calculated. The results showed that CircB3GNTL1 expression was up-regulated and miR-598 expression was up-regulated in gastric cancer tissues and cell lines; Knockdown circB3GNTL1 prevented proliferation and glutamine decomposition of the gastric cancer cells and induced apoptosis compared with normal para-cancers and gastric cancer cell lines. Results circB3GNTL1 can target and control miR-598 expression, and miR-598 can reverse the proliferation, apoptosis, and decomposition of glutamine from gastric cancer cells by knockdown circB3GNTL1. It was concluded that CirB3GNTL1 prevents decomposition of glutamines and induces apoptosis by controlling miR-598 in gastric cancer cells.
    Keywords:  apoptosis; circB3GNTL1; gastric cancer; glutaminolysis; miR-598; proliferation
  5. Anticancer Res. 2020 Dec;40(12): 6891-6897
      BACKGROUND/AIM: Cellular senescence is an important tumor-suppressive mechanism that arrests the cell cycle of damaged cells after diverse stresses. This study aimed to elucidate the role of mitochondrial glutamine (Gln) metabolism in senescence cell-fate decision after DNA damage.MATERIALS AND METHODS: β-galactosidase staining was used to determine senescence induction. The mechanistic target of rapamycin (mTOR) activity and p21 expression were examined by western blot. Cell proliferation and clonogenic growth were evaluated.
    RESULTS: Inhibition of mitochondrial Gln metabolism suppressed DNA damage-induced senescence, whereas increased Gln anaplerosis resulted in a profound induction of senescence. Mechanistically, Gln anaplerosis mediated senescence induction by activating mTOR signaling upon DNA damage. Importantly, enhancing Gln anaplerosis could reduce the emergence of proliferative subpopulations of cancer cells after exposure to non-lethal doses of chemotherapeutic agents.
    CONCLUSION: Mitochondrial Gln metabolism is an important regulator of DNA damage-induced senescence, which may be used for developing effective therapeutic approaches.
    Keywords:  DNA damage; Senescence; glutamine metabolism; mTOR
  6. Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30651-3. [Epub ahead of print]
      Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
    Keywords:  COPD; GYS1; gluconeogenesis; glycogen; glycogenesis; glycogenolysis; glycolysis; inflammation; neutrophil
  7. Comb Chem High Throughput Screen. 2020 Dec 04.
      BACKGROUND: Neurofibromatosis, also known as Von Recklinghausen disease, is a systemic and progressive genetic disease that primarily affects the skin, eyes, nervous system and bones. The disease can occur in a variety of ways and can vary from individuals. Metabolomic-based research using blood samples has enabled new diagnostic methods to be used in the diagnosis of various diseases, especially cancer. Among metabolites, profiling of plasma free amino acids (PFAA) is a promising approach because PFAAs bind all organ systems and play an important role in metabolism.OBJECTIVE: This study aimed to determine the characteristics of PFAA profiles in neurofibromatosis patients and the possibility of using them for early detection and treatment of the disease.
    METHOD: Patients with a diagnosis of Neurofibromatosis Type I confirmed by genetic analysis and healthy individuals of the same age group without any disease were included in the study. We analysed the nineteen plasma free amino acids (phenylalanine, proline, threonine, arginine, asparagine, cystine, valine, glutamate, tyrosine, serine, glutamine, glycine, tryptophane, leucine, lysine, methionine, isoleucine, aspartate and alanine) from neurofibromatosis Type I patients and control group by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Metabolism Laboratory of Harran University Research and Application Hospital. The results of the plasma free amino acid levels were divided into 3 groups as essential, semi-essential and non-essential. The differences of amino acid levels between groups were determined.
    RESULTS: Eight amino acid levels (methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate) were significantly altered in patients with neurofibromatosis type 1. In essential amino acids, methionine levels were significantly higher in the patient group than the control group. While the levels of arginine and glutamine in semi-essential amino acids were statistically significantly higher in the patient group, a significant decrease was observed in cystine and proline levels compared to the control group's amino acid levels. In non-essential amino acids group, asparagine, serine and aspartate amino acid levels were significantly higher in the patient group compared to the control group.
    CONCLUSION: The current research predicates that eight amino acids, nsmely methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate can be considered to be valuable biomarkers for neurofibromatosis type I. This present study is the first to build models for neurofibromatosis Type I screening using plasma free amino acids and the amino acid profile will guide the predicting of the complications that may occur during the course of the disease.
    Keywords:  Liquid chromatography tandem mass spectrometry (LC-MS/MS); Neurofibromatosis type 1; cystine; methionine; plasma amino acid; serine
  8. Front Cell Dev Biol. 2020 ;8 573747
      Calcium ion (Ca2+) signaling is critical to many physiological processes, and its kinetics and subcellular localization are tightly regulated in all cell types. All Ca2+ flux perturbations impact cell function and may contribute to various diseases, including cancer. Several modulators of Ca2+ signaling are attractive pharmacological targets due to their accessibility at the plasma membrane. Despite this, the number of specific inhibitors is still limited, and to date there are no anticancer drugs in the clinic that target Ca2+ signaling. Ca2+ dynamics are impacted, in part, by modifications of cellular metabolic pathways. Conversely, it is well established that Ca2+ regulates cellular bioenergetics by allosterically activating key metabolic enzymes and metabolite shuttles or indirectly by modulating signaling cascades. A coordinated interplay between Ca2+ and metabolism is essential in maintaining cellular homeostasis. In this review, we provide a snapshot of the reciprocal interaction between Ca2+ and metabolism and discuss the potential consequences of this interplay in cancer cells. We highlight the contribution of Ca2+ to the metabolic reprogramming observed in cancer. We also describe how the metabolic adaptation of cancer cells influences this crosstalk to regulate protumorigenic signaling pathways. We suggest that the dual targeting of these processes might provide unprecedented opportunities for anticancer strategies. Interestingly, promising evidence for the synergistic effects of antimetabolites and Ca2+-modulating agents is emerging.
    Keywords:  calcium; cancer; interplay; metabolism; signaling
  9. Life Sci. 2020 Dec 02. pii: S0024-3205(20)31605-2. [Epub ahead of print]265 118852
      AIMS: To discriminate metabolic biomarkers for diagnosis and risk prediction of multiple myeloma (MM) on a basis of metabolic characteristics in systemic circulation and local pathogenic niche.MAIN METHODS: A gas chromatography mass spectrometry-based untargeted metabolomics analysis was performed within the bone marrow (BM) supernatants and peripheral plasma from healthy donors and patients with MM.
    KEY FINDINGS: Distinct metabolic features between MM patients and healthy volunteers were profiled in both BM and plasma. Metabolic profiles of subgroups in which MM patients undergo high/medium/low risk displayed risk-dependent metabolic shift especially in BM. In MM patients, up-regulated glutamate level and down-regulated glutamine level in BM indicated enhanced glutamate metabolism which provided NH4+ for ammonia utilization. This resulted in increased level of urea and creatinine produced from urea cycle, arginine and proline metabolism in both BM and plasma collected from MM patients. The disorders of tricarboxylic acid cycle and carnitine synthesis were unique in BM of MM patients. Receiver operating characteristic curve analysis indicated that aspartate was a candidate plasma biomarker for diagnosis with the highest sensitivity and specificity in both BM and plasma. Threonine was identified as a preferential plasma biomarker for risk prediction due to significant relation with various risk indexes of MM in both BM and plasma.
    SIGNIFICANCE: The perturbed glutamate metabolism and carnitine synthesis in BM of MM patients provided a new sight on pathogenesis of MM. The plasma level of aspartate and threonine may become a preferential metabolic marker for diagnosis and risk prediction of MM, respectively.
    Keywords:  Biomarkers; Bone marrow; Metabolomics; Multiple myeloma; Peripheral plasma
  10. Mol Metab. 2020 Dec 02. pii: S2212-8778(20)30205-2. [Epub ahead of print] 101131
      BACKGROUND: Live kinase B1 (LKB1) is a tumor suppressor, which is mutated in Peutz-Jeghers syndrome (PJS) and in a variety of cancers. Lkb1 encodes serine-threonine kinase (STK) 11 that activates AMP-activated protein kinase (AMPK) and its 13 super-family members, hence regulating multiple biological processes, such as cell polarity, cell cycle arrest, embryo development, apoptosis, and bioenergetics metabolism. Increasing evidence has highlighted that deficiency of LKB1 in cancer cells induces extensive metabolic alterations, which promote tumorigenesis and development. On the other hand, LKB1 also participates in the maintenance of phenotypes and functions of normal cells through metabolic regulation.SCOPE OF REVIEW: Given the important role of LKB1 in metabolic regulation, we provide an overview of the association of metabolic alterations in glycolysis, aerobic oxidation, pentose phosphate pathway (PPP), gluconeogenesis, glutamine, lipid, and serine induced by aberrant LKB1 signal in tumor progression, non-neoplastic diseases, and functions of immune cells.
    MAJOR CONCLUSIONS: In this review, we summarize layers of evidence demonstrating that disordered metabolisms in glucose, glutamine, lipid, and serine caused by deficiency of LKB1 promote carcinogenesis and non-neoplastic diseases. The metabolic reprogramming resulted from the loss of LKB1 confers cancer cells with growth or survival advantages. Nevertheless, it also brings about a metabolic frangibility for LKB1-deficient cancer cells. The metabolic regulation of LKB1 also plays a vital role in maintaining cellular phenotype in the progression of non-neoplastic diseases. In addition, lipid metabolic regulation of LKB1 plays an important role in controlling the function, activity, proliferation, and differentiation of several types of immune cells. We conclude that in-depth knowledge of metabolic pathways under the regulation of LKB1 is conducive to the identification of therapeutic targets and the development of drug combination for the treatment of cancers, metabolic diseases, and the achievement of immunoregulation.
    Keywords:  Immune cell; LKB1; Lipid; Metabolism; Tumorigenesis
  11. Technol Cancer Res Treat. 2020 Jan-Dec;19:19 1533033820980113
      OBJECTIVE: This study aimed to investigate the correlation of L-asparaginase (L-asp) activity, anti-L-asp antibody, asparagine and glutamine levels with the risks of adverse events (AEs), especially anaphylaxis, in pediatric acute lymphoblastic leukemia (ALL) patients who underwent polyethylene glycol-conjugated L-asp (PEG-asp)-contained treatment.METHODS: Plasma samples were collected from 91 pediatric ALL patients who underwent PEG-asp-contained treatment on the 7th day after drug administration. Plasma L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level were detected. Meanwhile, AEs related to PEG-asp administration were recorded.
    RESULTS: AEs occurred in 13 (14.3%) patients, among which 7 (7.7%) patients had anaphylaxis, while another 6 patients had non-anaphylaxis AEs (including 4 (4.4%) patients who had acute pancreatitis, 1 (1.1%) patient who had abdominal pain and diarrhea, as well as 1 (1.1%) patient who had nausea and vomiting). L-asp activity was decreased, while asparagine and glutamine levels were increased in patients with AEs compared to patients without AEs, and ROC curves showed that they were correlated with higher AEs risk. Notably, further analyses revealed that L-asp activity, anti-L-asp antibody, asparagine and glutamine levels were highly correlated with anaphylaxis risk, but they were not associated with the risk of non-anaphylactic AEs.
    CONCLUSION: The measurement of L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level might assist the prevention of anaphylaxis-related AEs in pediatric ALL patients who underwent PEG-asp-contained treatment.
    Keywords:  L-asparaginase activity; adverse events; anaphylaxis; pediatric acute lymphoblastic leukemia; polyethylene glycol-conjugated L-asparaginase
  12. Cells. 2020 Dec 08. pii: E2635. [Epub ahead of print]9(12):
      The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is clinical and experimental evidence that an increased fructose intake promotes cancer growth. The precise mechanism, however, in which fructose induces tumor growth is still not fully understood. In this article, we present an overview of the metabolic pathways that utilize fructose and how fructose metabolism can sustain cancer cell proliferation. Although the degradation of fructose shares many of the enzymes and metabolic intermediates with glucose metabolism through glycolysis, glucose and fructose are metabolized differently. We describe the different metabolic fates of fructose carbons and how they are connected to lipogenesis and nucleotide synthesis. In addition, we discuss how the endogenous production of fructose from glucose via the polyol pathway can be beneficial for cancer cells.
    Keywords:  AKR1B1; HFCS; KHK; SORD; cancer metabolism; fructose metabolism; lipogenesis; pentose phosphate pathway; polyol pathway
  13. Front Pharmacol. 2020 ;11 544647
      Colorectal cancer is a common malignancy occurring in the digestive system, which is the third common cause of cancer mortality in developed countries. Shikonin, a naphthoquinone compound extracted from the root of Lithospermum erythrorhizon, is extensively reported to exert antitumor activity against various types of cancer. However, the systematic effect of shikonin in colon cancer remains poorly understood. In the present study, we evaluated the antitumor activity of shikonin in human colon cancer cells and the therapeutic effect on a xenograft mouse model. Transcriptomics and metabolomics were further integrated to provide a systematic perspective of the shikonin-induced antitumor mechanism. The results demonstrated that shikonin had a remarkable antitumor potency both in vitro and in vivo. Moreover, metabolic pathways, including the purine metabolism, amino acid metabolism, and glycerophospholipid metabolism, were perturbed and subsequently led to cell cycle arrest in the G2/M phase. In particular, the disturbance of purine metabolism may account for the major mechanism resulting from shikonin antitumor activity.
    Keywords:  colon cancer; metabolomics; purine metabolism; shikonin; transcriptomics
  14. Cells. 2020 Dec 03. pii: E2591. [Epub ahead of print]9(12):
      Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.
    Keywords:  cancer metabolism; iron; iron-sulfur cluster; mitochondria
  15. J Biol Chem. 2020 Dec 10. pii: jbc.RA120.015189. [Epub ahead of print]
      Glycoconjugates play a central role in several cellular processes and alteration in their composition is associated with numerous human pathologies. Substrates for cellular glycosylation are synthesized in the hexosamine biosynthetic pathway, which is controlled by the glutamine:fructose-6-phosphate amidotransfera-se (GFAT). Human isoform 2 GFAT (hGFAT2) has been implicated in diabetes and cancer; however, there is no information about structural and enzymatic properties of this enzyme. Here, we report a successful expression and purification of a catalytically active recombinant hGFAT2 (rhGFAT2) in E. coli cells fused or not to a HisTag at the C-terminal end. Our enzyme kinetics data suggest that hGFAT2 does not follow the expected ordered bi-bi mechanism, and performs the glucosamine-6-phosphate synthesis much more slowly than previously reported for other GFATs. In addition, hGFAT2 is able to isomerize fructose-6-phosphate into glucose-6-phosphate even in the presence of equimolar amounts of glutamine, which results in unproductive glutamine hydrolysis. Structural analysis of a three-dimensional model of rhGFAT2, corroborated by circular dichroism data, indicated the presence of a partially structured loop in the glutaminase domain, whose sequence is present in eukaryotic enzymes but absent in the E. coli homolog. Molecular dynamics simulations suggest that this loop is the most flexible portion of the protein, and plays a key role on conformational states of hGFAT2. Thus, our study provides the first comprehensive set of data on the structure, kinetics and mechanics of hGFAT2, which will certainly contribute to further studies on the (patho)physiology of hGFAT2.
    Keywords:  Glutamine:fructose-6-phosphate amidotransferase (GFAT); Nucleotide sugars; O-GlcNAcylation; UDP-GlcNAc; carbohydrate biosynthesis; carbohydrate metabolism; enzyme kinetics; glucosamine-6-phosphate synthase; glycosylation; hexosamine biosynthetic pathway (HBP); molecular dynamics; molecular modeling; protein structure
  16. Brain Behav Immun. 2020 Dec 02. pii: S0889-1591(20)32440-5. [Epub ahead of print]
      Neuroinflammation is the inflammatory responses that are involved in the pathogenesis of most CNS disorders. Glutaminase (GLS) is the enzyme that catalyzes the hydrolysis of glutamine to produce glutamate. Besides its well-known role in cellular metabolism and excitatory neurotransmission, GLS has recently been increasingly noticed to be up-regulated in activated microglia under pathological conditions. Furthermore, GLS overexpression induces microglial activation, extracellular vesicle secretion, and neuroinflammatory microenvironment formation, which, are compromised by GLS inhibitors in vitro and in vivo. These results indicate that GLS has more complicated implications in brain disease etiology than what are previously known. In this review, we introduce GLS isoforms, expression patterns in the body and the brain, and expression/activities regulation. Next, we discuss the metabolic and neurotransmission functions of GLS. Afterwards, we summarize recent findings of GLS-mediated microglial activation and pro-inflammatory extracellular vesicle secretion, which, in turns, induces neuroinflammation. Lastly, we provide a comprehensive discussion for the involvement of microglial GLS in the pathogenesis of various neurological disorders, indicating microglial GLS as a promising target to treat these diseases.
    Keywords:  Cellular metabolism; Extracellular vesicle; Microglia; Neuroinflammation; Neurological disorder