bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–03–12
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Metabolic Barriers to Glioblastoma Immunotherapy.
  2. Ovarian Cancer and Glutamine Metabolism.
  3. A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.
  4. ASS1-mediated reductive carboxylation of cytosolic glutamine confers ferroptosis resistance in cancer cells.
  5. The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.
  6. How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
  7. Primary cilia sense glutamine availability and respond via asparagine synthetase.
  8. Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
  9. L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.
  10. Metabolomics Analysis Reveals Novel Targets of Chemosensitizing Polyphenols and Omega-3 Polyunsaturated Fatty Acids in Triple Negative Breast Cancer Cells.
  11. Uric acid effects on glutathione metabolism estimated by induction of glutamate-cysteine ligase, glutathione reductase and glutathione synthetase in mouse J744A.1 macrophage cell line.
  12. Controlling the confounding effect of metabolic gene expression to identify actual metabolite targets in microsatellite instability cancers.
  1. Cancers (Basel). 2023 Feb 28. pii: 1519. [Epub ahead of print]15(5):
    Metabolic Barriers to Glioblastoma Immunotherapy.
    Nikita Choudhary, Robert C Osorio, Jun Y Oh, Manish K Aghi.
      Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.
    Keywords:  glioblastoma; glutamine metabolism; glycolysis; immunotherapy; lipid metabolism; metabolism; tryptophan metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15051519
  2. Int J Mol Sci. 2023 Mar 06. pii: 5041. [Epub ahead of print]24(5):
    Ovarian Cancer and Glutamine Metabolism.
    Zacharias Fasoulakis, Antonios Koutras, Thomas Ntounis, Ioannis Prokopakis, Paraskevas Perros, Athanasios Chionis, Ioakeim Sapantzoglou, Alexandros Katrachouras, Kyriakos Konis, Athina A Samara, Asimina Valsamaki, Vasileios-Chrysovalantis Palios, Panagiotis Symeonidis, Konstantinos Nikolettos, Athanasios Pagkalos, Sotirios Sotiriou, Marianna Theodora, Panos Antsaklis, Georgios Daskalakis, Emmanuel N Kontomanolis.
      Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there is a link between glutamine metabolism and the proliferation of cancer cells, demonstrating that glutamine metabolism is a vital mechanism for all cellular processes, including the development of cancer. Detailed knowledge regarding its degree of engagement in numerous biological processes across distinct cancer types is still lacking, despite the fact that such knowledge is necessary for comprehending the differentiating characteristics of many forms of cancer. This review aims to examine data on glutamine metabolism and ovarian cancer and identify possible therapeutic targets for ovarian cancer treatment.
    Keywords:  cancer cell; cancer treatment; glutamine; metabolism; ovarian cancer
    DOI:  https://doi.org/10.3390/ijms24055041
  3. Acta Pharm Sin B. 2023 Feb;13(2): 775-786
    A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.
    Qianhua Feng, Yutong Hao, Shuaiqi Yang, Xiaomin Yuan, Jing Chen, Yuying Mei, Lanlan Liu, Junbiao Chang, Zhenzhong Zhang, Lei Wang.
      The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.
    Keywords:  Cerium metal–organic framework; Drug delivery; Glutamine metabolism; Immunogenic tumor cell death; Immunotherapy; Lactate oxidase; Metabolic intervention; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.apsb.2022.10.021
  4. Cancer Res. 2023 Mar 09. pii: CAN-22-1999. [Epub ahead of print]
    ASS1-mediated reductive carboxylation of cytosolic glutamine confers ferroptosis resistance in cancer cells.
    Qiangsheng Hu, Jie Dai, Zheng Zhang, Huansha Yu, Jing Zhang, Xinsheng Zhu, Yi Qin, Lele Zhang, Peng Zhang.
      Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anti-cancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative TCA cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1-SREBP1-SCD5 axis to promote de novo monounsaturated fatty acid synthesis by utilizing acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared to either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1999
  5. Int J Mol Sci. 2023 Mar 03. pii: 4893. [Epub ahead of print]24(5):
    The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.
    Oxana Lungu, Denise Toscani, Jessica Burroughs-Garcia, Nicola Giuliani.
      The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functions, both in physiological and pathological malignant conditions. In particular, we focus on multiple myeloma (MM) bone disease, which is characterized by a severe imbalance in OB differentiation due to the presence of malignant plasma cells into the bone microenvironment. Here, we describe the most important metabolic alterations involved in the inhibition of OB formation and activity in MM patients.
    Keywords:  bone disease; glutamine; metabolism; multiple myeloma; osteoblasts
    DOI:  https://doi.org/10.3390/ijms24054893
  6. Cancers (Basel). 2023 Feb 23. pii: 1417. [Epub ahead of print]15(5):
    How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
    Zoé Daverio, Aneta Balcerczyk, Gilles J P Rautureau, Baptiste Panthu.
      Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.
    Keywords:  Warburg effect; glucose deprivation; lactic acidosis; metabolic symbiosis; tumour heterogeneity
    DOI:  https://doi.org/10.3390/cancers15051417
  7. Nat Metab. 2023 Mar 06.
    Primary cilia sense glutamine availability and respond via asparagine synthetase.
    Maria Elena Steidl, Elisa A Nigro, Anne Kallehauge Nielsen, Roberto Pagliarini, Laura Cassina, Matteo Lampis, Christine Podrini, Marco Chiaravalli, Valeria Mannella, Gianfranco Distefano, Ming Yang, Mariam Aslanyan, Giovanna Musco, Ronald Roepman, Christian Frezza, Alessandra Boletta.
      Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
    DOI:  https://doi.org/10.1038/s42255-023-00754-6
  8. Elife. 2023 Mar 08. pii: e78654. [Epub ahead of print]12
    Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
    Madeleine L Hart, Evan Quon, Anna-Lena B G Vigil, Ian A Engstrom, Oliver J Newsom, Kristian Davidsen, Pia Hoellerbauer, Samantha M Carlisle, Lucas B Sullivan.
      The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD+ to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss of function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.78654
  9. Oncogene. 2023 Mar 06.
    L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.
    Sho Tabata, Yasushi Kojima, Takeharu Sakamoto, Kaori Igarashi, Ko Umetsu, Takamasa Ishikawa, Akiyoshi Hirayama, Rie Kajino-Sakamoto, Naoya Sakamoto, Ken-Ichi Yasumoto, Keiichi Okano, Yasuyuki Suzuki, Shinichi Yachida, Masahiro Aoki, Tomoyoshi Soga.
      Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.
    DOI:  https://doi.org/10.1038/s41388-023-02632-7
  10. Int J Mol Sci. 2023 Feb 23. pii: 4406. [Epub ahead of print]24(5):
    Metabolomics Analysis Reveals Novel Targets of Chemosensitizing Polyphenols and Omega-3 Polyunsaturated Fatty Acids in Triple Negative Breast Cancer Cells.
    Blake R Rushing, Alleigh Wiggs, Sabrina Molina, Madison Schroder, Susan Sumner.
      Triple negative breast cancer (TNBC) is a subtype of breast cancer with typically poorer outcomes due to its aggressive clinical behavior and lack of targeted treatment options. Currently, treatment is limited to the administration of high-dose chemotherapeutics, which results in significant toxicities and drug resistance. As such, there is a need to de-escalate chemotherapeutic doses in TNBC while also retaining/improving treatment efficacy. Dietary polyphenols and omega-3 polyunsaturated fatty acids (PUFAs) have been demonstrated to have unique properties in experimental models of TNBC, improving the efficacy of doxorubicin and reversing multi-drug resistance. However, the pleiotropic nature of these compounds has caused their mechanisms to remain elusive, preventing the development of more potent mimetics to take advantage of their properties. Using untargeted metabolomics, we identify a diverse set of metabolites/metabolic pathways that are targeted by these compounds following treatment in MDA-MB-231 cells. Furthermore, we demonstrate that these chemosensitizers do not all target the same metabolic processes, but rather organize into distinct clusters based on similarities among metabolic targets. Common themes in metabolic targets included amino acid metabolism (particularly one-carbon and glutamine metabolism) and alterations in fatty acid oxidation. Moreover, doxorubicin treatment alone generally targeted different metabolites/pathways than chemosensitizers. This information provides novel insights into chemosensitization mechanisms in TNBC.
    Keywords:  drug response; metabolomics; omega-3 polyunsaturated fatty acids; polyphenols; triple negative breast cancer
    DOI:  https://doi.org/10.3390/ijms24054406
  11. Folia Med (Plovdiv). 2022 Oct 31. 64(5): 762-769
    Uric acid effects on glutathione metabolism estimated by induction of glutamate-cysteine ligase, glutathione reductase and glutathione synthetase in mouse J744A.1 macrophage cell line.
    Deyana Vankova, Yoana Kiselova-Kaneva, Diana Ivanova.
       INTRODUCTION: Elevated plasma levels of uric acid (UA) are considered an independent risk factor for hypertension, diabetes, cardiovascular disease, endothelial and vascular damage, obesity, and metabolic syndrome. Even physiological concentrations of soluble UA have been proved to induce gene expression of macrophage-secreted inflammatory cytokines and stimulate production of reactive oxygen species in mature adipocytes. UA is also described as a powerful endogenous plasma antioxidant, which reveals a paradox of duality for this parameter.
    Keywords:  glutamate-cysteine ligase glutathione peroxidase glutathione reductase glutathione synthetase uric acid
    DOI:  https://doi.org/10.3897/folmed.64.e65507
  12. Hum Genomics. 2023 Mar 06. 17(1): 18
    Controlling the confounding effect of metabolic gene expression to identify actual metabolite targets in microsatellite instability cancers.
    Chung-I Li, Yu-Min Yeh, Yi-Shan Tsai, Tzu-Hsuan Huang, Meng-Ru Shen, Peng-Chan Lin.
       BACKGROUND: The metabolome is the best representation of cancer phenotypes. Gene expression can be considered a confounding covariate affecting metabolite levels. Data integration across metabolomics and genomics to establish the biological relevance of cancer metabolism is challenging. This study aimed to eliminate the confounding effect of metabolic gene expression to reflect actual metabolite levels in microsatellite instability (MSI) cancers.
    METHODS: In this study, we propose a new strategy using covariate-adjusted tensor classification in high dimensions (CATCH) models to integrate metabolite and metabolic gene expression data to classify MSI and microsatellite stability (MSS) cancers. We used datasets from the Cancer Cell Line Encyclopedia (CCLE) phase II project and treated metabolomic data as tensor predictors and data on gene expression of metabolic enzymes as confounding covariates.
    RESULTS: The CATCH model performed well, with high accuracy (0.82), sensitivity (0.66), specificity (0.88), precision (0.65), and F1 score (0.65). Seven metabolite features adjusted for metabolic gene expression, namely, 3-phosphoglycerate, 6-phosphogluconate, cholesterol ester, lysophosphatidylethanolamine (LPE), phosphatidylcholine, reduced glutathione, and sarcosine, were found in MSI cancers. Only one metabolite, Hippurate, was present in MSS cancers. The gene expression of phosphofructokinase 1 (PFKP), which is involved in the glycolytic pathway, was related to 3-phosphoglycerate. ALDH4A1 and GPT2 were associated with sarcosine. LPE was associated with the expression of CHPT1, which is involved in lipid metabolism. The glycolysis, nucleotide, glutamate, and lipid metabolic pathways were enriched in MSI cancers.
    CONCLUSIONS: We propose an effective CATCH model for predicting MSI cancer status. By controlling the confounding effect of metabolic gene expression, we identified cancer metabolic biomarkers and therapeutic targets. In addition, we provided the possible biology and genetics of MSI cancer metabolism.
    Keywords:  CATCH model; Confounding effect; Metabolic gene; Metabolic targets; Metabolomic; Microsatellite instability
    DOI:  https://doi.org/10.1186/s40246-023-00465-9
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