bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒10‒30
twenty-two papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function.
  2. Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
  3. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.
  4. Glutamine metabolism and optimal immune and CNS function.
  5. Dialysis as a Novel Adjuvant Treatment for Malignant Cancers.
  6. circ_0025033 promotes ovarian cancer development via regulating the hsa_miR-370-3p/SLC1A5 axis.
  7. Juglone promotes antitumor activity against prostate cancer via suppressing glycolysis and oxidative phosphorylation.
  8. Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
  9. Targeting amino acid metabolism in cancer.
  10. Amino acid metabolism in primary bone sarcomas.
  11. Lack of Retinoblastoma Protein Shifts Tumor Metabolism from Glycolysis to OXPHOS and Allows the Use of Alternate Fuels.
  12. The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.
  13. Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.
  14. Combination strategies to target metabolic flexibility in cancer.
  15. Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
  16. TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma.
  17. Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
  18. IKCa channels control breast cancer metabolism including AMPK-driven autophagy.
  19. The thioredoxin system: balancing redox responses in immune cells and tumors.
  20. Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology.
  21. A multifaceted and feasible prognostic model of amino acid metabolism-related genes in the immune response and tumor microenvironment of head and neck squamous cell carcinomas.
  22. Modifying dietary amino acids in cancer patients.
  1. Cell Rep. 2022 10 25. pii: S2211-1247(22)01366-3. [Epub ahead of print]41(4): 111516
    NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function.
    Ajay Kumar, Emily L Yarosz, Anthony Andren, Li Zhang, Costas A Lyssiotis, Cheong-Hee Chang.
      Natural killer T (NKT) cells operate distinctly different metabolic programming from CD4 T cells, including a strict requirement for glutamine to regulate cell homeostasis. However, the underlying mechanisms remain unknown. Here, we report that at a steady state, NKT cells have higher glutamine levels than CD4 T cells and that NKT cells increase glutaminolysis on activation. Activated NKT cells use glutamine to fuel the tricarboxylic acid cycle and glutathione synthesis. In addition, glutamine-derived nitrogen enables protein glycosylation via the hexosamine biosynthesis pathway (HBP). Each of these branches of glutamine metabolism seems to be critical for NKT cell homeostasis and mitochondrial functions. Glutaminolysis and HBP differentially regulate interleukin-4 (IL-4) and interferon γ (IFNγ) production. Glutamine metabolism appears to be controlled by AMP-activated protein kinase (AMPK)-mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight a distinct metabolic requirement of NKT cells compared with CD4 T cells, which may have therapeutic implications in the treatment of certain nutrient-restricted diseases.
    Keywords:  CP: Immunology; HBP; PPP; ROS; glutathione; glycosylation; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2022.111516
  2. Cell Death Dis. 2022 Oct 27. 13(10): 906
    Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
    Rosario Yerbes, Rocío Mora-Molina, F Javier Fernández-Farrán, Laura Hiraldo, Abelardo López-Rivas, Carmen Palacios.
      Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL. In glutamine-depleted tumor cells, activation of the amino acid-sensing general control nonderepressible-2 kinase (GCN2) is responsible for TRAIL-R2 upregulation, caspase-8 activation, and apoptotic cell death. Interestingly, GCN2-dependent ISR signaling induced by methionine starvation also leads to TRAIL-R2 upregulation and apoptosis. Moreover, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids (NEAA). In addition, metabolic stress upon glutamine deprivation also results in GCN2-independent FLICE-inhibitory protein (FLIP) downregulation facilitating caspase-8 activation and apoptosis. Importantly, downregulation of the long FLIP splice form (FLIPL) and apoptosis upon glutamine deprivation are inhibited in the presence of a membrane-permeable α-ketoglutarate. Collectively, our data support a model in which limiting glutamine utilization in glutamine-addicted tumor cells triggers a previously unknown cell death mechanism regulated by GCN2 that involves the TRAIL-R2-mediated activation of the extrinsic apoptotic pathway.
    DOI:  https://doi.org/10.1038/s41419-022-05346-y
  3. Front Immunol. 2022 ;13 960226
    UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.
    Tiphaine Sancerni, Ophélie Renoult, Angèle Luby, Cédric Caradeuc, Véronique Lenoir, Mikael Croyal, Céline Ransy, Esther Aguilar, Catherine Postic, Gildas Bertho, Renaud Dentin, Carina Prip-Buus, Claire Pecqueur, Marie-Clotilde Alves-Guerra.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.
    Keywords:  UCP2; glutamine; leukemia; metabolism rewiring; metabolite carrier; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2022.960226
  4. Proc Nutr Soc. 2022 Oct 26. 1-20
    Glutamine metabolism and optimal immune and CNS function.
    Philip Newsholme, Vinicius Leonardo Sousa Diniz, Garron Thomas Dodd, Vinicius Cruzat.
      
    DOI:  https://doi.org/10.1017/S0029665122002749
  5. Cancers (Basel). 2022 Oct 15. pii: 5054. [Epub ahead of print]14(20):
    Dialysis as a Novel Adjuvant Treatment for Malignant Cancers.
    Sture Hobro, Anders Nilsson, Jan Sternby, Carl Öberg, Kristian Pietras, Håkan Axelson, Ana Carneiro, Sara Kinhult, Anders Christensson, Jonas Fors, Steven Maciejewski, Jason Knox, Innas Forsal, Linda Källquist, Viktoria Roos.
      Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels-thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.
    Keywords:  HDAC; cancer; chemotherapies; dialysis; immunotherapies; ketone bodies; radiotherapies; redox balance
    DOI:  https://doi.org/10.3390/cancers14205054
  6. Cell Mol Biol Lett. 2022 Oct 22. 27(1): 94
    circ_0025033 promotes ovarian cancer development via regulating the hsa_miR-370-3p/SLC1A5 axis.
    Huiping Ma, Shuyun Qu, Yao Zhai, Xiaofeng Yang.
      BACKGROUND: Circular RNAs (circRNAs) appear to be important modulators in ovarian cancer. We aimed to explore the role and mechanism of circ_0025033 in ovarian cancer.METHODS: qRT-PCR was conducted to determine circ_0025033, hsa_miR-370-3p, and SLC1A5 mRNA expression. Functional experiments were conducted, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, tube formation, xenograft tumor model assay, western blot analysis of protein levels, and analysis of glutamine metabolism using commercial kits. Their predicted interaction was confirmed using dual-luciferase reporter and RNA pull-down.
    RESULTS: circ_0025033 was upregulated in ovarian cancer; its knockdown induced proliferation, invasion, angiogenesis, glutamine metabolism, and apoptosis in vitro, and blocked tumor growth in vivo. circ_0025033 regulated ovarian cancer cellular behaviors via sponging hsa_miR-370-3p. In parallel, SLC1A5 might abolish the anti-ovarian cancer role of hsa_miR-370-3p. Furthermore, circ_0025033 affected SLC1A5 via regulating hsa_miR-370-3p.
    CONCLUSION: circ_0025033 might promote ovarian cancer progression via hsa_miR-370-3p/SLC1A5, providing an interesting insight into ovarian cancer tumorigenesis.
    Keywords:  Ovarian cancer; SLC1A5; circ_0025033; hsa_miR-370-3p
    DOI:  https://doi.org/10.1186/s11658-022-00364-2
  7. Phytother Res. 2022 Oct 24.
    Juglone promotes antitumor activity against prostate cancer via suppressing glycolysis and oxidative phosphorylation.
    Cheng Hu, Haiyue Xu, Zehao Li, Dandan Liu, Siqi Zhang, Fang Fang, Liguo Wang.
      The treatments currently used for prostate cancer (PC) do not meet clinical needs, and thus, new therapies with greater effectiveness are urgently required. Metabolic reprogramming of tumor cells is emerging as an exciting field for cancer therapy. Although the Warburg effect is a common feature of glucose metabolism in many cancers, PC cells have a unique metabolic phenotype. Non-neoplastic prostate cells show reduced oxidative phosphorylation (OXPHOS) because large, accumulated zinc inhibits citrate oxidation. During transformation, there are low levels of zinc in PC cells, and the tricarboxylic acid (TCA) cycle is reactivated. However, metastatic PC exhibits the Warburg effect. Due to metabolic differences in prostate tissue, targeting metabolic alterations in PC cells is an attractive therapeutic strategy. In this study, we investigated the effect of juglone on energy metabolism in PC cells. We found that juglone inhibited cell proliferation and induced apoptosis. Mechanistically, we demonstrated that juglone suppressed OXPHOS and glycolysis due to its inhibition of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) activity. Furthermore, downregulation of PFK and PK, but not HK contributed to the inhibition of these enzyme activities. The current study indicates that further development of juglone for PC treatment would be beneficial.
    Keywords:  Warburg effect; glycolysis; juglone; metabolomics; oxidative phosphorylation; prostate cancer
    DOI:  https://doi.org/10.1002/ptr.7631
  8. Cancers (Basel). 2022 Oct 18. pii: 5097. [Epub ahead of print]14(20):
    Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
    Lin Wang, Magdalena Cybula, Maria Rostworowska, Luyao Wang, Patryk Mucha, Magdalena Bulicz, Magdalena Bieniasz.
      We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention.
    Keywords:  SDHA; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers14205097
  9. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00109-5. [Epub ahead of print]373 37-79
    Targeting amino acid metabolism in cancer.
    Lucie Safrhansova, Katerina Hlozkova, Julia Starkova.
      Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.
    Keywords:  Amino acid metabolism; Arginine; Asparagine; Cancer; Cysteine; Methionine; Targeted therapy
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.001
  10. Front Oncol. 2022 ;12 1001318
    Amino acid metabolism in primary bone sarcomas.
    Jennifer A Jiménez, Elizabeth R Lawlor, Costas A Lyssiotis.
      Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care.
    Keywords:  Ewing sarcoma; amino acid metabolism; osteoblast; osteoclast; sarcoma; tumor metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.1001318
  11. Cells. 2022 Oct 11. pii: 3182. [Epub ahead of print]11(20):
    Lack of Retinoblastoma Protein Shifts Tumor Metabolism from Glycolysis to OXPHOS and Allows the Use of Alternate Fuels.
    Vishnu Suresh Babu, Gagan Dudeja, Deepak Sa, Anadi Bisht, Rohit Shetty, Stephane Heymans, Nilanjan Guha, Arkasubhra Ghosh.
      Mutations in the RB1 locus leading to a loss of functional Rb protein cause intraocular tumors, which uniquely affect children worldwide. These tumors demonstrate rapid proliferation, which has recently been shown to be associated with an altered metabolic signature. We found that retinoblastoma tumors and in-vitro models lack Hexokinase 1 (HK1) and exhibit elevated fatty acid oxidation. We show that ectopic expression of RB1 induces HK1 protein in Rb null cells, and both RB1 and HK1 can mediate a metabolic switch from OXPHOS to glycolysis with increased pyruvate levels, reduced ATP production and reduced mitochondrial mass. Further, cells lacking Rb or HK1 can flexibly utilize glutamine and fatty acids to enhance oxidative phosphorylation-dependent ATP generation, as revealed by metabolic and biochemical assays. Thus, loss of Rb and HK1 in retinoblastoma reprograms tumor metabolic circuits to enhance the glucose-independent TCA (tricarboxylic acid) cycle and the intermediate NAD+/NADH ratios, with a subsequent increase in fatty-acid derived L-carnitine to enhance mitochondrial OXPHOS for ATP production instead of glycolysis dependence. We also demonstrate that modulation of the Rb-regulated transcription factor E2F2 does not result in any of these metabolic perturbations. In conclusion, we demonstrate RB1 or HK1 as critical regulators of the cellular bioenergetic profile and identify the altered tumor metabolism as a potential therapeutic target for cancers lacking functional Rb protein.
    Keywords:  OCR; OXPHOS; energetics; glycolysis; metabolism; retinoblastoma
    DOI:  https://doi.org/10.3390/cells11203182
  12. Cancer Cell. 2022 Oct 26. pii: S1535-6108(22)00495-0. [Epub ahead of print]
    The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.
    Hengyou Weng, Feng Huang, Zhaojin Yu, Zhenhua Chen, Emily Prince, Yalin Kang, Keren Zhou, Wei Li, Jiacheng Hu, Chen Fu, Tursunjan Aziz, Hongzhi Li, Jingwen Li, Ying Yang, Li Han, Subo Zhang, Yuelong Ma, Mingli Sun, Huizhe Wu, Zheng Zhang, Mark Wunderlich, Sean Robinson, Daniel Braas, Johanna Ten Hoeve, Bin Zhang, Guido Marcucci, James C Mulloy, Keda Zhou, Hong-Fang Tao, Xiaolan Deng, David Horne, Minjie Wei, Huilin Huang, Jianjun Chen.
      N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.
    Keywords:  GPT2; IGF2BP2; MYC; SLC1A5; acute myeloid leukemia; glutamine metabolism; leukemia stem cells; m(6)A modification; mitochondria oxygen consumption; targeted therapy
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.004
  13. Nat Chem Biol. 2022 Oct 24.
    Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.
    Victor H Villar, Maria Francesca Allega, Ruhi Deshmukh, Tobias Ackermann, Mark A Nakasone, Johan Vande Voorde, Thomas M Drake, Janina Oetjen, Algernon Bloom, Colin Nixon, Miryam Müller, Stephanie May, Ee Hong Tan, Lars Vereecke, Maude Jans, Gillian Blancke, Daniel J Murphy, Danny T Huang, David Y Lewis, Thomas G Bird, Owen J Sansom, Karen Blyth, David Sumpton, Saverio Tardito.
      Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-Methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.
    DOI:  https://doi.org/10.1038/s41589-022-01154-9
  14. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00022-3. [Epub ahead of print]373 159-197
    Combination strategies to target metabolic flexibility in cancer.
    Jelena Krstic, Katharina Schindlmaier, Andreas Prokesch.
      Therapeutically interfering with metabolic pathways has great merit to curtail tumor growth because the demand for copious amounts of energy for growth-supporting biomass production is common to all cancer entities. A major impediment to a straight implementation of metabolic cancer therapy is the metabolic flexibility and plasticity of cancer cells (and their microenvironment) resulting in therapy resistance and evasion. Metabolic combination therapies, therefore, are promising as they are designed to target several energetic routes simultaneously and thereby diminish the availability of alternative substrates. Thus, dietary restrictions, specific nutrient limitations, and/or pharmacological interventions impinging on metabolic pathways can be combined to improve cancer treatment efficacy, to overcome therapy resistance, or even act as a preventive measure. Here, we review the most recent developments in metabolic combination therapies particularly highlighting in vivo reports of synergistic effects and available clinical data. We close with identifying the challenges of the field (metabolic tumor heterogeneity, immune cell interactions, inter-patient variabilities) and suggest a "metabo-typing" strategy to tailor evidence-based metabolic combination therapies to the energetic requirements of the tumors and the patient's nutritional habits and status.
    Keywords:  Cancer; Combination therapy; Dietary restriction; Metabolic flexibility
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.03.001
  15. Subcell Biochem. 2022 ;100 3-65
    Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
    Swagata Adhikari, Deblina Guha, Chitra Mohan, Shravanti Mukherjee, Jessica K Tyler, Chandrima Das.
      Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.
    Keywords:  Acetyl-CoA; Carbohydrate metabolism; DNMTs; Epigenetics; Glycolytic flux; HATs; HDACs; HDM; HMT; Hypoxia; Metabolic reprogramming; Metastasis; OXPHOS; Oncometabolites; SAM; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_1
  16. Theranostics. 2022 ;12(16): 7032-7050
    TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma.
    Shixue Yang, Jixing Zhao, Xiaoteng Cui, Qi Zhan, Kaikai Yi, Qixue Wang, Menglin Xiao, Yanli Tan, Biao Hong, Chuan Fang, Chunsheng Kang.
      Rationale: Glioblastoma (GBM) displays a complex metabolic reprogramming in cancer cells. Adenosine triphosphate (ATP) is one of the central mediators of cell metabolism and signaling. GBM cells generate ATP by glycolysis and the tricarboxylic acid (TCA) cycle associated with oxidative phosphorylation (OXPHOS) through the breaking-down of pyruvate or fatty acids to meet the growing energy demand of cancer cells. Therefore, it's urgent to develop novel treatments targeting energy metabolism to hinder tumor cell proliferation in GBM. Methods: Non-targeted metabolomic profiling analysis was utilized to evaluate cell metabolic reprogramming using a small molecule inhibitor (SMI) EPIC-0412 treatment. Cellular oxygen consumption rate (OCR) and the total proton efflux rate (PER), as well as ATP concentration, were tracked to study metabolic responses to specifically targeted inhibitors, including EPIC-0412, arachidonyl trifluoromethyl ketone (AACOCF3), and 2 deoxy-D-glucose (2-DG). Cancer cell proliferation was assessed by CCK-8 measurements and colony formation assay. Additionally, flow cytometry, immunoblotting (IB), and immunofluorescence (IF) analyses were performed with GBM cells to understand their tumorigenic properties under treatments. Finally, the anticancer effects of this combination therapy were evaluated in the GBM mouse model by convection-enhanced delivery (CED). Results: We found that SMI EPIC-0412 could effectively perturb the TCA cycle, which participated in the combination therapy of cytosolic phospholipase A2 (cPLA2)-inhibitor AACOCF3, and hexokinase II (HK2)-inhibitor 2-DG to disrupt the GBM energy metabolism for targeted metabolic treatments. ATP production was significantly declined in glioma cells when treated with monotherapy (EPIC-0412 or AACOCF3), dual therapy (EPIC-0412 + AACOCF3), or triple therapy (EPIC-0412 + AACOCF3 +2-DG) regimen. Our experiments revealed that these therapies hindered glioma cell proliferation and growth, leading to the reduction in ATP production and G0/G1 cell cycle arrest. We demonstrated that the combination therapy effectively extended the survival of cerebral tumor-bearing mice. Conclusion: Our findings indicate that the TCA-phospholipid-glycolysis metabolism axis can be blocked by specific inhibitors that significantly disrupt the tumor energy metabolism and suppress tumor proliferation in vitro and in vivo, suggesting that targeting ATP synthesis inhibition in cancer cells might be an attractive therapeutic avenue in GBM management.
    Keywords:  ATP production; convection-enhanced delivery.; energy metabolism; glioblastoma
    DOI:  https://doi.org/10.7150/thno.74197
  17. Biomolecules. 2022 Oct 02. pii: 1412. [Epub ahead of print]12(10):
    Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
    Pierre Jacquet, Angélique Stéphanou.
      This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities.
    Keywords:  Warburg effect; metabolic landscape; metabolic reprogramming; metabolic switch; reverse Warburg
    DOI:  https://doi.org/10.3390/biom12101412
  18. Cell Death Dis. 2022 Oct 27. 13(10): 902
    IKCa channels control breast cancer metabolism including AMPK-driven autophagy.
    Dominic Gross, Helmut Bischof, Selina Maier, Katharina Sporbeck, Andreas L Birkenfeld, Roland Malli, Peter Ruth, Tassula Proikas-Cezanne, Robert Lukowski.
      Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K+- and Ca2+- homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca2+- and K+-dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy.
    DOI:  https://doi.org/10.1038/s41419-022-05329-z
  19. Eur J Immunol. 2022 Oct 25.
    The thioredoxin system: balancing redox responses in immune cells and tumors.
    Jonathan Muri, Manfred Kopf.
      The thioredoxin (TRX) system is an important contributor to cellular redox balance and regulates cell growth, apoptosis, gene expression, and antioxidant defense in nearly all living cells. Oxidative stress, the imbalance between reactive oxygen species (ROS) and antioxidants, can lead cell death and tissue damage, thereby contributing to ageing and to the development of several diseases, including cardiovascular and allergic diseases, diabetes, and neurological disorders. Targeting its activity is also considered as a promising strategy in the treatment of cancer. Over the past years, immunologists have established an essential function of TRX for activation, proliferation, and responses in T cells, B cells, and macrophages. Upon activation, immune cells rearrange their redox system and activate the TRX pathway to promote proliferation through sustainment of nucleotide biosynthesis and to support inflammatory responses in myeloid cells by allowing NF-κB and NLRP3 inflammasome responses. Consequently, targeting the TRX system may therapeutically be exploited to inhibit immune responses in inflammatory conditions. In this review, we summarize recent insights revealing key roles of the TRX pathway in immune cells in health and disease, and lessons learnt for cancer therapy. This article is protected by copyright. All rights reserved.
    Keywords:  TRX system ⋅ Immunoregulation ⋅ ROS ⋅ Cancer ⋅ Cellular redox
    DOI:  https://doi.org/10.1002/eji.202249948
  20. Metabolites. 2022 Sep 28. pii: 918. [Epub ahead of print]12(10):
    Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology.
    Sirui Chen, Jingjing Jiang, Ao Shen, Ying Miao, Yunfeng Cao, Ying Zhang, Peiyu Cong, Peng Gao.
      Amino acids (AAs) are indispensable building blocks of diverse bio-macromolecules as well as functional regulators for various metabolic processes. The fact that cancer cells live with a voracious appetite for specific AAs has been widely recognized. Glioma is one of the most lethal malignancies occurring in the central nervous system. The reprogrammed metabolism of AAs benefits glioma proliferation, signal transduction, epigenetic modification, and stress tolerance. Metabolic alteration of specific AAs also contributes to glioma immune escape and chemoresistance. For clinical consideration, fluctuations in the concentrations of AAs observed in specific body fluids provides opportunities to develop new diagnosis and prognosis markers. This review aimed at providing an extra dimension to understanding glioma pathology with respect to the rewired AA metabolism. A deep insight into the relevant fields will help to pave a new way for new therapeutic target identification and valuable biomarker development.
    Keywords:  amino acid; biomarker; glioma; metabolism; metabolomics
    DOI:  https://doi.org/10.3390/metabo12100918
  21. Front Oncol. 2022 ;12 996222
    A multifaceted and feasible prognostic model of amino acid metabolism-related genes in the immune response and tumor microenvironment of head and neck squamous cell carcinomas.
    Wei Li, Zhefei Zou, Ning An, Mingwei Wang, Xiguo Liu, Zhidan Mei.
      We investigated the role of amino acid metabolism (AAM) in head and neck squamous cell carcinoma (HNSCC) tissues to explore its prognostic value and potential therapeutic strategies. A risk score based on four AAM-related genes (AMG) was constructed that could predict the prognosis of HNSCC. These four genes were up-regulated in HNSCC tissues and might act as oncogenes. Internal validation in The Cancer Genome Atlas (TCGA) by bootstrapping showed that patients with high-risk scores had a poorer prognosis than patients with low-risk scores, and this was confirmed in the Gene Expression Omnibus (GEO) cohort. There were also differences between the high-risk and low-risk groups in clinical information and different anatomical sites such as age, sex, TNM stage, grade stage, surgery or no surgery, chemotherapy, radiotherapy, no radiotherapy, neck lymph node dissection or not, and neck lymphovascular invasion, larynx, overlapping lesion of lip, and oral cavity and pharynx tonsil of overall survival (OS). Immune-related characteristics, tumor microenvironment (TME) characteristics, and immunotherapy response were significantly different between high- and low-risk groups. The four AMGs were also found to be associated with the expression of markers of various immune cell subpopulations. Therefore, our comprehensive approach revealed the characterization of AAM in HNSCC to predict prognosis and guide clinical therapy.
    Keywords:  amino acid metabolism; bootstrap; head and neck squamous cell carcinoma; immune; prognostic; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.996222
  22. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00009-0. [Epub ahead of print]373 1-36
    Modifying dietary amino acids in cancer patients.
    Josephine Connolly-Schoonen, Steven F Biamonte, Lorraine Danowski, David C Montrose.
      Limiting nutrient utilization by cancer cells in order to disrupt their metabolism and suppress their growth represents a promising approach for anti-cancer therapy. Recently, studies demonstrating the anti-neoplastic effects of lowering amino acid (AA) availability have opened up an exciting and quickly growing field of study. Although intracellular synthesis can often provide the AAs necessary to support cancer cells, diet and the tumor microenvironment can also be important sources. In fact, studies carried out in vitro and in animal tumor models have supported the anti-cancer potential of restricting exogenous sources of AAs. However the potential benefit of reducing AA intake in cancer patients requires further investigation. Furthermore, implementation of such an approach clinically, even if proven useful, could be challenging. In the enclosed review, we (1) summarize the pre-clinical studies showing the anti-tumorigenic effects of restricting exogenously available AAs, including through reducing dietary protein, (2) consider the role of microbiota in this process, (3) report on current recommendations for protein intake in cancer patients and studies that applied these guidelines, and (4) propose considerations for studies to test the potential therapeutic benefit of reducing protein/AA consumption in patients with cancer.
    Keywords:  Chemotherapy; Diet; Muscle; Protein; Tumor
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.02.004
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