bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021‒07‒25
fourteen papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Cancers (Basel). 2021 Jul 12. pii: 3485. [Epub ahead of print]13(14):
      Metabolic reprogramming is a well described hallmark of cancer. Oncogenic stimuli and the microenvironment shape the metabolic phenotype of cancer cells, causing pathological modifications of carbohydrate, amino acid and lipid metabolism that support the uncontrolled growth and proliferation of cancer cells. Conversely, metabolic alterations in cancer can drive changes in genetic programs affecting cell proliferation and differentiation. In recent years, the role of non-coding RNAs in metabolic reprogramming in cancer has been extensively studied. Here, we review this topic, with a focus on glucose, glutamine, and lipid metabolism and point to some evidence that metabolic alterations occurring in cancer can drive changes in non-coding RNA expression, thus adding an additional level of complexity in the relationship between metabolism and genetic programs in cancer cells.
    Keywords:  Warburg effect; cancer metabolism; glutaminolysis; glycolysis; lipid metabolism; long non-coding RNAs; metabolic reprogramming
  2. Clin Cancer Res. 2021 Jul 20. pii: clincanres.CCR-21-1204-E.2021. [Epub ahead of print]
      PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A Phase 1 study of the oral, first-in-class, glutaminase inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity.EXPERIMENTAL DESIGN: Dose escalation by 3 +3 design was followed by exploratory tumor-/biomarker-specific cohorts.
    RESULTS: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% glutaminase inhibition in platelets at plasma exposures >300 nM; >75% tumoral glutaminase inhibition; and significant increase in circulating glutamine. RP2D was defined at 800mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).
    CONCLUSIONS: Telaglenastatis safe with a favorable PK/PD profile and signal of antitumor activity supporting further clinical development.
  3. Redox Biol. 2021 Jul 11. pii: S2213-2317(21)00224-X. [Epub ahead of print]46 102065
      Although glucose, through pentose phosphate pathway (PPP), is the main source to generate NADPH, solid tumors are often deprived of glucose, hence alternative metabolic pathways to maintain NADPH homeostasis in cancer cells are required. Here, we report that lactate and glutamine support NADPH production via isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), respectively, under glucose-deprived conditions. Isotopic tracing demonstrates that lactate participates in the formation of isocitrate. Malate derived from glutamine in mitochondria shuttles to cytosol to produce NADPH. In cells cultured in the absence of glucose, knockout of IDH1 and ME1 decreases NADPH/NADP+ and GSH/GSSG, increases ROS level and facilitates cell necrosis. In 4T1 murine breast tumors, knockout of ME1 retards tumor growth in vivo, with combined ME1/IDH1 knockout more strongly suppressing tumor growth. Our findings reveal two alternative NADPH-producing pathways that cancer cells use to resist glucose starvation, reflecting the metabolic plasticity and flexibility of cancer cells adapting to nutrition stress.
    Keywords:  Glucose deprivation; Glutamine; IDH1; Lactate; ME1; NADPH
  4. Front Med. 2021 Jul 24.
      Metabolic reprogramming, such as abnormal utilization of glucose, addiction to glutamine, and increased de-novo lipid synthesis, extensively occurs in proliferating cancer cells, but the underneath rationale has remained to be elucidated. Based on the concept of the degree of reduction of a compound, we have recently proposed a calculation termed as potential of electron transfer (PET), which is used to characterize the degree of electron redistribution coupled with metabolic transformations. When this calculation is combined with the assumed model of electron balance in a cellular context, the enforced selective reprogramming could be predicted by examining the net changes of the PET values associated with the biochemical pathways in anaerobic metabolism. Some interesting properties of PET in cancer cells were also discussed, and the model was extended to uncover the chemical nature underlying aerobic glycolysis that essentially results from energy requirement and electron balance. Enabling electron transfer could drive metabolic reprogramming in cancer metabolism. Therefore, the concept and model established on electron transfer could guide the treatment strategies of tumors and future studies on cellular metabolism.
    Keywords:  aerobic glycolysis; cancer metabolism; cell proliferation; metabolic reprogramming; potential of electron transfer
  5. Front Cell Dev Biol. 2021 ;9 714755
      Within the bone marrow hematopoietic cells are in close connection with mesenchymal stromal cells (MSCs), which influence the behavior and differentiation of normal or malignant lymphoid and myeloid cells. Altered cell metabolism is a hallmark of cancer, and changes in nutrient pools and fluxes are important components of the bidirectional communication between MSCs and hematological cancer cells. Among nutrients, amino acids play a significant role in cancer progression and chemo-resistance. Moreover, selected types of cancer cells are extremely greedy for glutamine, and significantly deplete the extracellular pool of the amino acid. As a consequence, this influences the behavior of MSCs in terms of either cytokine/chemokine secretion or differentiation potential. Additionally, a direct nutritional interaction exists between MSCs and immune cells. In particular, selected subpopulations of lymphocytes are dependent upon selected amino acids, such as arginine and tryptophan, for full differentiation and competence. This review describes and discusses the nutritional interactions existing in the neoplastic bone marrow niche between MSCs and other cell types, with a particular emphasis on cancer cells and immune cells. These relationships are discussed in the perspective of potential novel therapeutic strategies based on the interference on amino acid metabolism or intercellular fluxes.
    Keywords:  amino acid transport system; arginine; asparagine; bone marrow; glutamine; leukemia; mesenchymal stromal cell; tryptophan
  6. Leuk Lymphoma. 2021 Jul 19. 1-12
      Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene (iaaA) with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.
    Keywords:  Acute lymphoblastic leukemia; amino acid; microbiome; pediatric; pegaspargase
  7. Amino Acids. 2021 Jul 22.
      Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.
    Keywords:  Amino acids; Asparaginase; Cancer; Metabolism; Oncology
  8. Int J Mol Sci. 2021 Jul 09. pii: 7379. [Epub ahead of print]22(14):
      The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.
    Keywords:  cisplatin resistance; metabolism; oxidative metabolism; reactive oxygen species
  9. Front Cell Dev Biol. 2021 ;9 683276
      Glioblastoma is a primary malignant brain tumor with a median survival under 2 years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection, and drives inevitable recurrence. While most studies to date have focused on pathways that enhance the invasiveness of tumor cells in the brain microenvironment as the primary driving forces behind GBM's ability to invade adjacent tissues, more recent studies have identified a role for adaptations in cellular metabolism in GBM invasion. Metabolic reprogramming allows invasive cells to generate the energy necessary for colonizing surrounding brain tissue and adapt to new microenvironments with unique nutrient and oxygen availability. Historically, enhanced glycolysis, even in the presence of oxygen (the Warburg effect) has dominated glioblastoma research with respect to tumor metabolism. More recent global profiling experiments, however, have identified roles for lipid, amino acid, and nucleotide metabolism in tumor growth and invasion. A thorough understanding of the metabolic traits that define invasive GBM cells may provide novel therapeutic targets for this devastating disease. In this review, we focus on metabolic alterations that have been characterized in glioblastoma, the dynamic nature of tumor metabolism and how it is shaped by interaction with the brain microenvironment, and how metabolic reprogramming generates vulnerabilities that may be ripe for exploitation.
    Keywords:  brain tumor; glioblastoma; invasion; metabolism; microenvironment
  10. Cancers (Basel). 2021 Jul 03. pii: 3351. [Epub ahead of print]13(13):
      Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical "cell death" machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
    Keywords:  cancer metabolism; cell death; drug resistance; mitochondria
  11. Biochim Biophys Acta Rev Cancer. 2021 Jul 16. pii: S0304-419X(21)00089-5. [Epub ahead of print]1876(2): 188592
      Patients with pancreatic cancer have an abysmal survival rate. The poor prognosis of pancreatic cancer is due to the difficulty of making an early diagnosis, high rate of metastasis, and frequent chemoresistance. In recent years, as a self-regulatory procedure within cells, the effect and mechanism of autophagy have been explored. Dysregulated autophagy serves as a double-edged sword in cancer development in which autophagy inhibits cancer initiation but promotes cancer progression. After tumor formation, activation of autophagy can induce epithelial-mesenchymal transition, regulate metabolism, specifically glutamine usage and the glycolytic process, and mediate drug resistance in pancreatic cancer. Multiple genes, RNA molecules, proteins, and certain drugs exert antitumor effects by inhibiting autophagy-mediated drug resistance. Several clinical trials have combined autophagy inhibitors with chemotherapeutic drugs in pancreatic cancer treatment, some of which have shown promising results. In conclusion, autophagy plays a vital role in pancreatic cancer progression and deserves further study.
    Keywords:  Autophagy; Chemoresistance; Epithelial-mesenchymal transition; Glucose metabolism; Immunotherapy; Pancreatic cancer
  12. Front Oncol. 2021 ;11 694526
      Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.
    Keywords:  GCN2; general control non-derepressible 2; mTORC1; myeloid leukemias; non-essential amino acid
  13. Sci Rep. 2021 Jul 19. 11(1): 14680
      Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC-MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.
  14. Front Cell Dev Biol. 2021 ;9 655731
      The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.
    Keywords:  autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients