bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–01–29
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. The role of metabolic reprogramming in pancreatic cancer chemoresistance.
  2. Gallic acid markedly stimulates GLUT1-mediated glucose uptake by the AsPC-1 pancreatic cancer cell line.
  3. An updated patent review of glutaminase inhibitors (2019-2022).
  4. Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
  5. Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
  6. Targeted metabolomics analysis identified the role of FOXA1 in the change in glutamate-glutamine metabolic pattern of BaP malignantly transformed 16HBE cells.
  7. Targeting glutamine use in RCC.
  8. The role of cancer cell bioenergetics in dormancy and drug resistance.
  9. Dysregulation and epigenetic reprogramming of NRF2 signaling axis promote acquisition of cisplatin resistance and metastasis in Head and Neck Squamous Cell Carcinoma.
  10. When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective.
  11. Multiple oxidative post-translational modifications of human glutamine synthetase mediate peroxynitrite-dependent enzyme inactivation and aggregation.
  12. Hypoxia signaling in cancer: Implications for therapeutic interventions.
  13. The antioxidant glutathione.
  1. Front Pharmacol. 2022 ;13 1108776
    The role of metabolic reprogramming in pancreatic cancer chemoresistance.
    Chang Liu, Changfeng Li, Yuanda Liu.
      Pancreatic cancer is characterized by hidden onset, high malignancy, and early metastasis. Although a few cases meet the surgical indications, chemotherapy remains the primary treatment, and the resulting chemoresistance has become an urgent clinical problem that needs to be solved. In recent years, the importance of metabolic reprogramming as one of the hallmarks of cancers in tumorigenesis has been validated. Metabolic reprogramming involves glucose, lipid, and amino acid metabolism and interacts with oncogenes to affect the expression of key enzymes and signaling pathways, modifying the tumor microenvironment and contributing to the occurrence of drug tolerance. Meanwhile, the mitochondria are hubs of the three major nutrients and energy metabolisms, which are also involved in the development of drug resistance. In this review, we summarized the characteristic changes in metabolism during the progression of pancreatic cancer and their impact on chemoresistance, outlined the role of the mitochondria, and summarized current studies on metabolic inhibitors.
    Keywords:  chemoresistance; fatty acid synthesis; glutamine metabolism; glycolysis; metabolic reprogramming; pancreatic cancer
    DOI:  https://doi.org/10.3389/fphar.2022.1108776
  2. Can J Physiol Pharmacol. 2023 Jan 20.
    Gallic acid markedly stimulates GLUT1-mediated glucose uptake by the AsPC-1 pancreatic cancer cell line.
    Sílvia M Torres, Francisca P Carmo, Luís C Monteiro, Cláudia Silva, Nelson Andrade, Fátima Martel.
      Phenolic acids are recognized as chemopreventive and chemotherapeutic agents. Altered glucose and glutamine metabolism are recognized hallmarks of cancer cells. We aimed to test the influence of phenolic acids on glucose and glutamine cellular uptake by a breast (MCF-7) and a pancreatic (AsPC-1) cancer cell line. Several phenolic acids (caffeic, ferrulic, proctocatechuic, coumaric and gallic acid) affected 3H-glutamine and/or 3H-deoxy-d-glucose (3H-DG) uptake. Gallic acid (100 µM) caused a 3-fold increase in 3H-DG uptake by AsPC-1 cells, associated with a 3.7-fold increase in lactic acid production. Gallic acid stimulated GLUT1-mediated 3H-DG uptake and increased the affinity of this transporter for 3H-DG. We further verified that gallic acid does not change GLUT1 transcription rates and cellular redox state and that its effect does not involve PI3K, mTOR and MAP kinases and is not associated with a proproliferative effect. Gallic acid also increased 3H-DG uptake by MCF-7 cells, although less potently. Further investigation is necessary to elucidate the cellular pathways involved in this effect of gallic acid.
    Keywords:  GLUT1; Gallic acid; glucose; pancreatic cancer
    DOI:  https://doi.org/10.1139/cjpp-2022-0260
  3. Expert Opin Ther Pat. 2023 Jan 25.
    An updated patent review of glutaminase inhibitors (2019-2022).
    Danni Wang, Xiaohong Li, Guangyue Gong, Yulong Lu, Ziming Guo, Rui Chen, Huidan Huang, Zhiyu Li, Jinlei Bian.
       INTRODUCTION: The kidney-type glutaminase (GLS1), a key enzyme controlling the hydrolysis of glutamine to glutamate to resolve the 'glutamine addiction' of cancer cells, has been shown to play a central role in supporting cancer growth and proliferation. Therefore, the inhibition of GLS1 as a novel cancer treating strategy is of great interest.
    AREAS COVERED: This review covers recent patents (2019-present) involving GLS1 inhibitors, which are mostly focused on their chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.
    EXPERT OPINION: : Currently, despite significant efforts, the search for potent GLS1 inhibitors has not resulted in the development of compounds for therapeutic application. Most recent patents and literature focus on GLS1 inhibitors IPN60090 and DRP104, which have entered clinical trials. While other patent disclosures during this period have not generated any drug candidates, the clinical update will inform the potential of these inhibitors as promising therapeutic agents either as single or as combination interventions.
    Keywords:  GLS1; SAR; antitumor; glutamine metabolism; small molecule
    DOI:  https://doi.org/10.1080/13543776.2023.2173573
  4. Cell Death Dis. 2023 Jan 26. 14(1): 61
    Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
    Vrushank Bhatt, Taijin Lan, Wenping Wang, Jerry Kong, Eduardo Cararo Lopes, Jianming Wang, Khoosheh Khayati, Akash Raju, Michael Rangel, Enrique Lopez, Zhixian Sherrie Hu, Xuefei Luo, Xiaoyang Su, Jyoti Malhotra, Wenwei Hu, Sharon R Pine, Eileen White, Jessie Yanxiang Guo.
      LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.
    DOI:  https://doi.org/10.1038/s41419-023-05592-8
  5. Cell Rep. 2023 Jan 27. pii: S2211-1247(23)00052-9. [Epub ahead of print]42(2): 112041
    Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
    Ying Liu, Kejia Liu, Rick F Thorne, Ronghua Shi, Qingyuan Zhang, Mian Wu, Lianxin Liu.
      Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
    Keywords:  CP: Cancer; CP: Metabolism; PTMs; SENP2; SUMOylation; TCA cycle; acetylation; metabolic stress; mitochondria; oxidative phosphorylation; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112041
  6. Toxicol Appl Pharmacol. 2023 Jan 23. pii: S0041-008X(23)00040-6. [Epub ahead of print] 116402
    Targeted metabolomics analysis identified the role of FOXA1 in the change in glutamate-glutamine metabolic pattern of BaP malignantly transformed 16HBE cells.
    Yunkun Xing, Zhiyu Liu, Xue Ma, Chuan Zhou, Yu Wang, Biyun Yao, Juanling Fu, Yanmin Qi, Peng Zhao.
      The carcinogenic mechanism of benzo[a]pyrene (BaP) is far from being elucidated. FOXA1 has been confirmed to play an oncogenic role in BaP-transformed cell THBEc1. To explore the changes in amino acid metabolic patterns, especially glutamate-glutamine (Glu-Gln) metabolic pattern caused by BaP-induced transformation and the possible role FOXA1 might play in it, we compared amino acid metabolic characteristics between THBEc1 cells and control 16HBE cells using a targeted metabolomics method and determined the effects of FOXA1 knockout on the amino acid metabolic pattern using FOXA1 knockout cell THBEc1-ΔFOXA1-c34. The amino acid metabolic patterns of THBEc1 and 16HBE cells were different, which was manifested by the differential consumption of 18 amino acids and the difference in the intracellular content of 21 amino acids. The consumption and intracellular content of Glu and Gln are different between the two types of cells, accompanied by upregulation of FOXA1, GLUL, SLC1A3, SLC1A4, SLC1A5 and SLC6A14, and downregulation of FOXA2 and GPT2 in THBEc1 cells. FOXA1 knockout changed the consumption of 19 amino acids and the intracellular content of 21 amino acids and reversed the metabolic pattern of Glu and the changes in FOXA2, GLUL, SLC1A3 and SLC6A14 in THBEc1 cells. Additionally, FOXA1 knockout inhibited cell proliferation and further increased the dependence of THBEc1 cells on Glu. In conclusion, FOXA1 knockout partially reversed the change in Glu-Gln metabolism caused by BaP-induced transformation by upregulating the expression of GLUL and SLC1A3. Our findings provide a clue for the possible role of FOXA1 in amino acid metabolism regulation.
    Keywords:  Benzo[a]Pyrene; FOXA1; Glutamate-Glutamine Metabolic Change; Lung cancer; THBEc1 Cells
    DOI:  https://doi.org/10.1016/j.taap.2023.116402
  7. Nat Rev Nephrol. 2023 Jan 24.
    Targeting glutamine use in RCC.
    Monica Wang.
      
    DOI:  https://doi.org/10.1038/s41581-023-00684-2
  8. Cancer Metastasis Rev. 2023 Jan 25.
    The role of cancer cell bioenergetics in dormancy and drug resistance.
    Steven Tau, Todd W Miller.
      While anti-cancer drug treatments are often effective for the clinical management of cancer, these treatments frequently leave behind drug-tolerant persister cancer cells that can ultimately give rise to recurrent disease. Such persistent cancer cells can lie dormant for extended periods of time, going undetected by conventional clinical means. Understanding the mechanisms that such dormant cancer cells use to survive, and the mechanisms that drive emergence from dormancy, is critical to the development of improved therapeutic strategies to prevent and manage disease recurrence. Cancer cells often exhibit metabolic alterations compared to their non-transformed counterparts. An emerging body of evidence supports the notion that dormant cancer cells also have unique metabolic adaptations that may offer therapeutically targetable vulnerabilities. Herein, we review mechanisms through which cancer cells metabolically adapt to persist during drug treatments and develop drug resistance. We also highlight emerging therapeutic strategies to target dormant cancer cells via their metabolic features.
    Keywords:  Cancer; Energy; Fatty acid; Glucose; Metabolism; Tumor
    DOI:  https://doi.org/10.1007/s10555-023-10081-7
  9. Clin Cancer Res. 2023 Jan 23. pii: CCR-22-2747. [Epub ahead of print]
    Dysregulation and epigenetic reprogramming of NRF2 signaling axis promote acquisition of cisplatin resistance and metastasis in Head and Neck Squamous Cell Carcinoma.
    Abdullah A Osman, Emre Arslan, Mason Bartels, Chieko Michikawa, Antje Lindemann, Katarzyna Tomczak, Wangjie Yu, Vlad Sandulache, Wencai Ma, Li Shen, Jing Wang, Anand K Singh, Mitchell J Frederick, Nakia D Spencer, Jeffrey Kovacs, Timothy Heffernan, William F Symmans, Kunal Rai, Jeffrey N Myers.
       PURPOSE: CDDP based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCCs), despite a high rate of treatment failures, acquired resistance and subsequent aggressive behavior. The purpose of this study was to delineate the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.
    EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF-2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole exome sequencing, single cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms Results: Implantation of CDDP resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wtKEAP1 genes re-sensitized resistant cells to CDDP and decreased distant metastasis. Finally, treatment with inhibitor of GLS1, a NRF2 target gene, alleviated CDDP resistance.
    CONCLUSIONS: CDDP resistance and development of distant metastasis are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP resistant head and neck tumors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2747
  10. Front Oncol. 2022 ;12 1054233
    When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective.
    Zhiqiang Zhang, Chaohui Bao, Lu Jiang, Shan Wang, Kankan Wang, Chang Lu, Hai Fang.
      Resistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.
    Keywords:  cancer drug resistance; metabolic reprogramming; metabolomics; single-cell metabolomics; spatial metabolomics
    DOI:  https://doi.org/10.3389/fonc.2022.1054233
  11. J Biol Chem. 2023 Jan 23. pii: S0021-9258(23)00073-X. [Epub ahead of print] 102941
    Multiple oxidative post-translational modifications of human glutamine synthetase mediate peroxynitrite-dependent enzyme inactivation and aggregation.
    Nicolás Campolo, Mauricio Mastrogiovanni, Michele Mariotti, Federico M Issoglio, Darío Estrin, Per Hägglund, Tilman Grune, Michael J Davies, Silvina Bartesaghi, Rafael Radi.
      Glutamine synthetase (GS), which catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia, is a ubiquitous and conserved enzyme that plays a pivotal role in nitrogen metabolism across all life domains. In vertebrates, GS is highly expressed in astrocytes, where its activity sustains the glutamate-glutamine cycle at glutamatergic synapses and is thus essential for maintaining brain homeostasis. In fact, decreased GS levels or activity have been associated with neurodegenerative diseases, with these alterations attributed to oxidative post-translational modifications of the protein, in particular tyrosine nitration. In this study, we expressed and purified human GS (HsGS) and performed an in-depth analysis of its oxidative inactivation by peroxynitrite (ONOO-) in vitro. We found that ONOO- exposure led to a dose-dependent loss of HsGS activity, the oxidation of cysteine, methionine and tyrosine residues and also the nitration of tryptophan and tyrosine residues. Peptide mapping by LC-MS/MS through combined H216O/H218O trypsin digestion identified up to 10 tyrosine nitration sites and five types of dityrosine cross-links; these modifications were further scrutinized by structural analysis. Tyrosine residues 171, 185, 269, 283 and 336 were the main nitration targets; however, tyrosine-to-phenylalanine HsGS mutants revealed that their sole nitration was not responsible for enzyme inactivation. In addition, we observed that ONOO- induced HsGS aggregation and activity loss. Thiol oxidation was a key modification to elicit aggregation, as it was also induced by hydrogen peroxide treatment. Taken together, our results indicate that multiple oxidative events at various sites are responsible for the inactivation and aggregation of human GS.
    Keywords:  aggregation; dityrosine; free radicals; glutamine synthetase; hydrogen peroxide; nitrotyrosine; oxidants; peroxynitrite; thiol oxidation
    DOI:  https://doi.org/10.1016/j.jbc.2023.102941
  12. MedComm (2020). 2023 Feb;4(1): e203
    Hypoxia signaling in cancer: Implications for therapeutic interventions.
    Yan Zhuang, Kua Liu, Qinyu He, Xiaosong Gu, Chunping Jiang, Junhua Wu.
      Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.
    Keywords:  hyperoxia; hypoxia‐inducible factor (HIF); immunotherapy; targeted theraphy; tumor hypoxia
    DOI:  https://doi.org/10.1002/mco2.203
  13. Vitam Horm. 2023 ;pii: S0083-6729(22)00071-1. [Epub ahead of print]121 109-141
    The antioxidant glutathione.
    Diana A Averill-Bates.
      Reduced glutathione (GSH) is an essential non-enzymatic antioxidant in mammalian cells. GSH can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzymes such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to GSH oxidation to glutathione disulfide (GSSG). GSSG is converted back to GSH by glutathione reductase and cofactor NADPH. GSH can regenerate vitamin E following detoxification reactions of vitamin E with lipid peroxyl radicals (LOO). GSH is a cofactor for GST during detoxification of electrophilic substances and xenobiotics. Dicarbonyl stress induced by methylglyoxal and glyoxal is alleviated by glyoxalase enzymes and GSH. GSH regulates redox signaling through reversible oxidation of critical protein cysteine residues by S-glutathionylation. GSH is involved in other cellular processes such as protein folding, protecting protein thiols from oxidation and crosslinking, degradation of proteins with disulfide bonds, cell cycle regulation and proliferation, ascorbate metabolism, apoptosis and ferroptosis.
    Keywords:  Antioxidant; Glutathione; Glutathione S-transferase; Glutathione peroxidase; Glyoxalases; Hydrogen peroxide; Lipid peroxidation; Oxidative distress; Peroxiredoxin; S-glutathionylation
    DOI:  https://doi.org/10.1016/bs.vh.2022.09.002
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