bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒06‒12
eleven papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Zeolitic imidazolate framework-based nanoparticles for the cascade enhancement of cancer chemodynamic therapy by targeting glutamine metabolism.
  2. Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation.
  3. Nicotinamide-N-methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma.
  4. Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis.
  5. Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
  6. mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma.
  7. Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway.
  8. AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.
  9. Cancer-Induced Metabolic Rewiring of Tumor Endothelial Cells.
  10. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy.
  11. Metabolic reprogramming: a bridge between aging and tumorigenesis.
  1. Nanoscale. 2022 Jun 08.
    Zeolitic imidazolate framework-based nanoparticles for the cascade enhancement of cancer chemodynamic therapy by targeting glutamine metabolism.
    Hui Jian, Yun Zhang, Junyue Wang, Zhenxiang Chen, Tingyi Wen.
      The reprogrammed amino acid metabolism maintains the powerful antioxidant defense and DNA damage repair capacity of cancer cells, which could promote their escape from reactive oxygen species (ROS)-induced damage and inevitably diminish the efficacy of ROS-based therapies. Herein, we propose a strategy to enhance the effect of chemodynamic therapy (CDT) via glutaminolysis-targeted inhibition for cancer cells dependent on abnormal glutamine metabolism. To screen optimum drugs targeting glutamine metabolism, transcriptomic analysis is performed to identify predictive biomarkers. Eventually, telaglenastat (CB-839) is used to block mitochondrial glutaminase 1 (GLS 1) in basal-like breast cancer and loaded into the developed iron-doped zeolitic imidazolate frameworks (ZIF(Fe) NPs) to form ZIF(Fe)&CB nanoparticles, which are able to co-deliver Fe2+ and CB-839 into the tumor. CB-839 induced-glutaminolysis inhibition not only reduces intracellular antioxidants (glutathione, taurine) to amplify Fe2+-induced oxidative stress, but also decreases nucleotide pools (e.g., adenosine, dihydroorotate) to incur the deficiency of building blocks for DNA damage repair, thereby promoting the cell-killing effect of CDT. In vivo assessments further confirm the enhanced anticancer performance and good biocompatibility of ZIF(Fe)&CB nanoparticles. This study provides a promising strategy for the development and improvement of ROS-based anticancer nanosystems.
    DOI:  https://doi.org/10.1039/d2nr01736a
  2. Front Immunol. 2022 ;13 880262
    Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation.
    Qiang Yu, Honghu Tu, Xueyi Yin, Chang Peng, Chuanyun Dou, Wenhua Yang, Wenbiao Wu, Xiaotong Guan, Jia Li, Hexin Yan, Yi Zang, Haowen Jiang, Qiang Xia.
      Background: Autoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model.Methods: AIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting.
    Results: JHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling.
    Conclusions: We proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.
    Keywords:  SLC7A5; T cells activation and differentiation; autoimmune hepatitis (AIH); glutamine metabolism; mTOR signaling
    DOI:  https://doi.org/10.3389/fimmu.2022.880262
  3. Clin Transl Med. 2022 Jun;12(6): e883
    Nicotinamide-N-methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma.
    Anna Reustle, Lena-Sophie Menig, Patrick Leuthold, Ute Hofmann, Viktoria Stühler, Christian Schmees, Michael Becker, Mathias Haag, Verena Klumpp, Stefan Winter, Florian A Büttner, Steffen Rausch, Jörg Hennenlotter, Falko Fend, Marcus Scharpf, Arnulf Stenzl, Jens Bedke, Matthias Schwab, Elke Schaeffeler.
      BACKGROUND: The metabolic enzyme nicotinamide-N-methyltransferase (NNMT) is highly expressed in various cancer entities, suggesting tumour-promoting functions. We systematically investigated NNMT expression and its metabolic interactions in clear cell renal cell carcinoma (ccRCC), a prominent RCC subtype with metabolic alterations, to elucidate its role as a drug target.METHODS: NNMT expression was assessed in primary ccRCC (n = 134), non-tumour tissue and ccRCC-derived metastases (n = 145) by microarray analysis and/or immunohistochemistry. Findings were validated in The Cancer Genome Atlas (kidney renal clear cell carcinoma [KIRC], n = 452) and by single-cell analysis. Expression was correlated with clinicopathological data and survival. Metabolic alterations in NNMT-depleted cells were assessed by nontargeted/targeted metabolomics and extracellular flux analysis. The NNMT inhibitor (NNMTi) alone and in combination with the inhibitor 2-deoxy-D-glucose for glycolysis and BPTES (bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl-sulfide) for glutamine metabolism was investigated in RCC cell lines (786-O, A498) and in two 2D ccRCC-derived primary cultures and three 3D ccRCC air-liquid interface models.
    RESULTS: NNMT protein was overexpressed in primary ccRCC (p = 1.32 × 10-16 ) and ccRCC-derived metastases (p = 3.92 × 10-20 ), irrespective of metastatic location, versus non-tumour tissue. Single-cell data showed predominant NNMT expression in ccRCC and not in the tumour microenvironment. High NNMT expression in primary ccRCC correlated with worse survival in independent cohorts (primary RCC-hazard ratio [HR] = 4.3, 95% confidence interval [CI]: 1.5-12.4; KIRC-HR = 3.3, 95% CI: 2.0-5.4). NNMT depletion leads to intracellular glutamine accumulation, with negative effects on mitochondrial function and cell survival, while not affecting glycolysis or glutathione metabolism. At the gene level, NNMT-depleted cells upregulate glycolysis, oxidative phosphorylation and apoptosis pathways. NNMTi alone or in combination with 2-deoxy-D-glucose and BPTES resulted in inhibition of cell viability in ccRCC cell lines and primary tumour and metastasis-derived models. In two out of three patient-derived ccRCC air-liquid interface models, NNMTi treatment induced cytotoxicity.
    CONCLUSIONS: Since efficient glutamine utilisation, which is essential for ccRCC tumours, depends on NNMT, small-molecule NNMT inhibitors provide a novel therapeutic strategy for ccRCC and act as sensitizers for combination therapies.
    Keywords:  NNMT; NNMTi; glutamine; metabolism; metastasis; oxphos; renal cell carcinoma
    DOI:  https://doi.org/10.1002/ctm2.883
  4. Cancers (Basel). 2022 May 27. pii: 2655. [Epub ahead of print]14(11):
    Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis.
    Mariam Markouli, Dimitrios Strepkos, Kostas A Papavassiliou, Athanasios G Papavassiliou, Christina Piperi.
      Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.
    Keywords:  DNA; Krebs cycle; TCA cycle; acetylation; glioblastoma; glioma; gluconeogenesis; glutamine; glycolysis; histones; methylation; microRNAs; oxidative phosphorylation; pentose phosphate pathway
    DOI:  https://doi.org/10.3390/cancers14112655
  5. Nat Cancer. 2022 Jun 09.
    Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
    Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.
      Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.
    DOI:  https://doi.org/10.1038/s43018-022-00393-y
  6. Cancers (Basel). 2022 Jun 02. pii: 2766. [Epub ahead of print]14(11):
    mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma.
    Uddin Md Nazim, Kausik Bishayee, Jieun Kang, Dongkwan Yoo, Sung-Oh Huh, Ali Sadra.
      Studies in targeting metabolism in cancer cells have shown the flexibility of cells in reprogramming their pathways away from a given metabolic block. Such behavior prompts a combination drug approach in targeting cancer metabolism, as a single compound may not address the tumor intractability. Overall, mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated as enabling metabolic escape in the case of a glycolysis block. From a library of compounds, the tyrosine kinase inhibitor ponatinib was screened to provide optimal reduction in metabolic activity in the production of adenosine triphosphate (ATP), pyruvate, and lactate for multiple myeloma cells; however, these cells displayed increasing levels of oxidative phosphorylation (OXPHOS), enabling them to continue generating ATP, although at a slower pace. The combination of ponatinib with the mTORC1 inhibitor, sirolimus, blocked OXPHOS; an effect also manifested in activity reductions for hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) glycolysis enzymes. There were also remarkably higher levels of reactive oxygen species (ROS) produced in mouse xenografts, on par with increased glycolytic block. The combination of ponatinib and sirolimus resulted in synergistic inhibition of tumor xenografts with no overt toxicity in treated mice for kidney and liver function or maintaining weight.
    Keywords:  glycolysis; mTORC1; multiple myeloma; ponatinib; sirolimus
    DOI:  https://doi.org/10.3390/cancers14112766
  7. Eur Respir J. 2022 Jun 09. pii: 2200062. [Epub ahead of print]
    Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway.
    Xiucheng Liu, Hao Qin, Zheng Li, Yin Lv, Shoujie Feng, Wei Zhuang, Xiaoyu Quan, Chen Guo, Chen Chang, Zhang Hao.
      The lack of knowledge about the effect of inspiratory hyperoxia (IH) on the lung-specific tumor microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that IH has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo Our results reveal that IH treatment (60% O2, 6 h·day-1) not only has no tumor progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. We also combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by IH treatment. These findings are relevant to the debate on the perils, promises and antitumor effect of IH, especially for patients with lung cancer.
    DOI:  https://doi.org/10.1183/13993003.00062-2022
  8. Cells. 2022 May 31. pii: 1800. [Epub ahead of print]11(11):
    AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.
    Inês Belo do Nascimento, Marie Verfaillie, Gamze Ates, Pauline Beckers, Virginie Joris, Nathalie Desmet, Ann Massie, Emmanuel Hermans.
      Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) in the control of cell metabolism, we have examined its implication in the adaptation of astrocyte functions in response to a metabolic stress triggered by glucose deprivation. We genetically modified the astrocyte-like C6 cell line to silence AMPK activity by overexpressing a dominant negative mutant of its catalytic subunit. Upon glucose deprivation, we found that C6 cells maintain stable ATP levels and glutamate uptake capacity, highlighting their resilience during metabolic stress. In the same conditions, cells with silenced AMPK activity showed a reduction in motility, metabolic activity, and ATP levels, indicating that their adaptation to stress is compromised. The rate of ATP production remained, however, unchanged by AMPK silencing, suggesting that AMPK mostly influences energy consumption during stress conditions in these cells. Neither AMPK modulation nor prolonged glucose deprivation impaired glutamate uptake. Together, these results indicate that AMPK contributes to the adaptation of astrocyte metabolism triggered by metabolic stress, but not to the regulation of glutamate transport.
    Keywords:  ATP; astrocyte; glucose deprivation; glutamate transporter; metabolic stress
    DOI:  https://doi.org/10.3390/cells11111800
  9. Cancers (Basel). 2022 May 31. pii: 2735. [Epub ahead of print]14(11):
    Cancer-Induced Metabolic Rewiring of Tumor Endothelial Cells.
    Jacopo Lidonnici, Massimo M Santoro, Roxana E Oberkersch.
      Cancer is a leading cause of death worldwide. If left untreated, tumors tend to grow and spread uncontrolled until the patient dies. To support this growth, cancer cells need large amounts of nutrients and growth factors that are supplied and distributed to the tumor tissue by the vascular system. The aberrant tumor vasculature shows deep morphological, molecular, and metabolic differences compared to the blood vessels belonging to the non-malignant tissues (also referred as normal). A better understanding of the metabolic mechanisms driving the differences between normal and tumor vasculature will allow the designing of new drugs with a higher specificity of action and fewer side effects to target tumors and improve a patient's life expectancy. In this review, we aim to summarize the main features of tumor endothelial cells (TECs) and shed light on the critical metabolic pathways that characterize these cells. A better understanding of such mechanisms will help to design innovative therapeutic strategies in healthy and diseased angiogenesis.
    Keywords:  endothelial metabolism in cancer; tumor endothelial cells; tumor vasculature
    DOI:  https://doi.org/10.3390/cancers14112735
  10. World J Stem Cells. 2022 Apr 26. 14(4): 267-286
    Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy.
    Qi Zhang, Wei Li.
      Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
    Keywords:  Amino acid metabolism; Cancer stem cell; Resistance; Self-renewal
    DOI:  https://doi.org/10.4252/wjsc.v14.i4.267
  11. Mol Oncol. 2022 Jun 05.
    Metabolic reprogramming: a bridge between aging and tumorigenesis.
    Stanislav Drapela, Didem Ilter, Ana P Gomes.
      Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build up of metabolic by-products and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age-driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell-autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, anti-aging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard-of-care anti-cancer therapies.
    Keywords:  Aging; cellular energetics; immune response; metabolic reprogramming; tumorigenesis
    DOI:  https://doi.org/10.1002/1878-0261.13261
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