bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021‒01‒31
sixteen papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Cancers (Basel). 2021 Jan 27. pii: 483. [Epub ahead of print]13(3):
      Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism.
    Keywords:  GLS; PDAC; TFEB; glutamine
  2. Theranostics. 2021 ;11(5): 2048-2057
      Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. With a designation of WHO Grade IV, it is also the most lethal primary brain tumor with a median survival of just 15 months. This is often despite aggressive treatment that includes surgical resection, radiation therapy, and chemotherapy. Based on the poor outcomes and prevalence of the tumor, the demand for innovative therapies continues to represent a pressing issue for clinicians and researchers. In terms of therapies targeting metabolism, the prevalence of the Warburg effect has led to a focus on targeting glucose metabolism to halt tumor progression. While glucose is the dominant source of growth substrate in GBM, a number of unique metabolic pathways are exploited in GBM to meet the increased demand for replication and progression. In this review we aim to explore how metabolites from fatty acid oxidation, the urea cycle, the glutamate-glutamine cycle, and one-carbon metabolism are shunted toward energy producing pathways to meet the high energy demand in GBM. We will also explore how the process of autophagy provides a reservoir of nutrients to support viable tumor cells. By so doing, we aim to establish a foundation of implicated metabolic mechanisms supporting growth and tumorigenesis of GBM within the literature. With the sparse number of therapeutic interventions specifically targeting metabolic pathways in GBM, we hope that this review expands further insight into the development of novel treatment modalities.
    Keywords:  arginine; autophagy; fatty acids; glioblastoma; glutamine; metabolism
  3. Biology (Basel). 2021 Jan 23. pii: 85. [Epub ahead of print]10(2):
      The pentose phosphate pathway (PPP) plays an essential role in the metabolism of breast cancer cells for the management of oxidative stress and the synthesis of nucleotides. 6-phosphogluconate dehydrogenase (6PGD) is one of the key enzymes of the oxidative branch of PPP and is involved in nucleotide biosynthesis and redox maintenance status. Here, we aimed to analyze the functional importance of 6PGD in a breast cancer cell model. Inhibition of 6PGD in MCF7 reduced cell proliferation and showed a significant decrease in glucose consumption and an increase in glutamine consumption, resulting in an important alteration in the metabolism of these cells. No difference in reactive oxygen species (ROS) production levels was observed after 6PGD inhibition, indicating that 6PGD, in contrast to glucose 6-phosphate dehydrogenase, is not involved in redox balance. We found that 6PGD inhibition also altered the stem cell characteristics and mammosphere formation capabilities of MCF7 cells, opening new avenues to prevent cancer recurrance after surgery or chemotherapy. Moreover, inhibition of 6PGD via chemical inhibitor S3 resulted in an induction of senescence, which, together with the cell cycle arrest and apoptosis induction, might be orchestrated by p53 activation. Therefore, we postulate 6PGD as a novel therapeutic target to treat breast cancer.
    Keywords:  6PGD; breast cancer; cancer metabolism; pentose phosphate pathway
  4. Front Cell Dev Biol. 2020 ;8 603837
      Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism of amino acids are aberrantly upregulated in many cancers that display addiction to particular amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress. Thus, targeting amino acid metabolism is becoming a potential therapeutic strategy for cancer patients. In this review, we will systematically summarize the recent progress of amino acid metabolism in malignancy and discuss their interconnection with mammalian target of rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth and immunity, and ferroptosis. Finally, we will highlight the potential therapeutic applications.
    Keywords:  amino acids (AAs); cancer; epigenetic; ferroptosis; mTORC (mammalian target of rapamycin kinase complex); metabolism; tumor growth; tumor immunity
  5. Dis Markers. 2021 ;2021 8850990
      Background: Glutamine metabolism is considered an important metabolic phenotype of proliferating tumor cells.Objective: The objective of this study was to investigate the expression of glutamine metabolism-related and amino acid transporter proteins in adrenal cortical neoplasms (ACNs) and pheochromocytomas (PCCs) in the adrenal gland.
    Methods: A tissue microarray was constructed for 132 cases of ACN (115 cases of adrenal cortical adenoma and 17 cases of adrenal cortical carcinoma) and 189 cases of PCC. Immunohistochemical staining for glutamine metabolism-related proteins GLS1 and GDH and amino acid transporter proteins SLC1A5, SLC7A5, and SLC7A11 as well as SDHB was performed and compared with clinicopathologic parameters.
    Results: The expression levels of GLS (p < 0.001), SLC7A5 (p = 0.049), and SDHB (p = 0.007) were higher in ACN than in PCC, whereas the expression levels of SLC1A5 (p < 0.001) and SLC7A11 (p < 0.001) were higher in PCC than in ACN. In ACN, GLS positivity was associated with a higher Fuhrman grade (p = 0.009), and SLC1A5 positivity was associated with SDHB positivity (p = 0.004) and a clear cell proportion < 25% (p = 0.010). SDHB negativity was also associated with tumor cell necrosis (p = 0.007). In PCC, SLC7A11 positivity was associated with nonnorepinephrine type (p = 0.008). In Kaplan-Meier analysis, patients with GLS positivity (p = 0.039) and SDHB negativity (p = 0.005) had significantly shorter overall survival in ACN. In PCC patients with a GAPP score ≥ 3, GLS positivity (p = 0.001) and SDHB positivity (p = 0.001) were associated with shorter disease-free survival, whereas GLS positivity (p = 0.004) was also associated with shorter overall survival.
    Conclusions: The expression of glutamine metabolism-related and amino acid transporter proteins in ACN and PCC is distinct and associated with prognosis.
  6. Int J Mol Sci. 2021 Jan 27. pii: 1258. [Epub ahead of print]22(3):
      The use of immune checkpoint inhibitors (ICI) in treating cancer has revolutionized the approach to eradicate cancer cells by reactivating immune responses. However, only a subset of patients benefits from this treatment; the majority remains unresponsive or develops resistance to ICI therapy. Increasing evidence suggests that metabolic machinery in the tumor microenvironment (TME) plays a role in the development of ICI resistance. Within the TME, nutrients and oxygen are scarce, forcing immune cells to undergo metabolic reprogramming to adapt to harsh conditions. Cancer-induced metabolic deregulation in immune cells can attenuate their anti-cancer properties, but can also increase their immunosuppressive properties. Therefore, targeting metabolic pathways of immune cells in the TME may strengthen the efficacy of ICIs and prevent ICI resistance. In this review, we discuss the interactions of immune cells and metabolic alterations in the TME. We also discuss current therapies targeting cellular metabolism in combination with ICIs for the treatment of cancer, and provide possible mechanisms behind the cellular metabolic rewiring that may improve clinical outcomes.
    Keywords:  cancer niche; immune checkpoint inhibitor; immuno-metabolism; immunotherapy; metabolic reprogramming; metabolism; resistance; tumor microenvironment
  7. Front Neurosci. 2020 ;14 613225
      Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.
    Keywords:  GLAST/EAAT1; GLT1/EAAT2; carbon tetrachloride; glial cell; glutamine synthetase; liver injury
  8. Redox Biol. 2021 Jan 21. pii: S2213-2317(21)00018-5. [Epub ahead of print] 101870
      Cancer cells display abnormal metabolic activity as a result of activated oncogenes and loss of tumor suppressor genes. The Warburg Effect is a common metabolic feature of cancer that involves a preference for aerobic glycolysis over oxidative phosphorylation to generate ATP and building blocks for biosynthesis. However, emerging evidence indicates that mitochondrial metabolic pathways are also reprogrammed in cancer and play vital roles in bioenergetics, biosynthesis, and managing redox homeostasis. The mitochondria act a central hub for metabolic pathways that generate ATP and building blocks for lipid, nucleic acid and protein biosynthesis. However, mitochondrial respiration is also a leading source of reactive oxygen species that can damage cellular organelles and trigger cell death if levels become too high. In general, cancer cells are reported to have higher levels of reactive oxygen species than their non-cancerous cells of origin, and therefore must employ diverse metabolic strategies to prevent oxidative stress. However, mounting evidence indicates that the metabolic profiles between proliferative and disseminated cancer cells are not the same. In this review, we will examine mitochondrial metabolic pathways, such as glutaminolysis, that proliferative and disseminated cancer cells utilize to control their redox status.
    Keywords:  Cancer progression; Glutaminolysis; Mitochondria metabolism; Redox homeostasis
  9. Free Radic Biol Med. 2021 Jan 25. pii: S0891-5849(21)00032-0. [Epub ahead of print]
      Mediated by chaperon proteins, protein misfolding plays a crucial role in cancer pathogenesis. Chaperonin Containing TCP1 Subunit 3 (CCT3) is one of eight subunits forming eukaryotic chaperons that catalyzes correct folding of the proteins employed in cell division, proliferation, and apoptosis pathway. Moreover, CCT3 expression increases responsively with carcinogenesis. However, how CCT3 drives the cancerous process has not been documented. Here we probed the mechanistic and functional interactions between CCT3 and apoptotic pathways and cell stressors. First, we profiled CCT3 expression levels of different 16 cell lines and found that CCT3 expression levels of CRL-2329 and PC3 were significantly increased. Then, we suppressed CCT3 levels in CRL-2329 and PC3 lines by miR-24-3p, miR-128-3p, and miR-149-5p mimics, and measured apoptotic response of the cell lines to the knockdown of CCT3 by acridine orange/ethidium bromide and Annexin V/PI staining, cell-cycle and mitochondria membrane potential (MMP) analyses, intracellular reactive oxygen species (ROS) measurement and analysis of expression levels of the apoptotic genes. After having suppressed CCT3, the cell cycle was arrested in the G0/G1 phase, MMP was impaired, and the intracellular ROS level was increased. These signs of apoptotic flux were corroborated by morphological images, statistically enhanced expression levels of the apoptotic pathway modulators and intracellular free amino acids profile. The free amino acid profile, which is heavily implicated in energy metabolism and cell division, is fluctuated in the progress of canceration. Strikingly, suppressed CCT3 shifted intracellular levels of glutamine, beta-alanine, glycine, serin, asparagine and sarcosine, which are employed in energy metabolism. Consequently, miRNA-mediated CCT3 suppression spur apoptosis by unbalancing the homeostasis in intracellular ROS and the profile of free amino acids in energy metabolism. Taken together, we anticipate that miRNA-mediated CCT3 suppression might provide a "dual therapeutic strategy" through conventional cellular toxicity as well as energy withdrawal.
    Keywords:  Apoptosis; CCT3; Chaperone; miR-128-3p; miR-149-5p; miR-24-3p
  10. Biology (Basel). 2021 Jan 22. pii: 83. [Epub ahead of print]10(2):
      Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer.
    Keywords:  GPX4; SLC7A11; cyst(e)ine metabolism; ferroptosis; glutathione metabolism; iron metabolism; lipid peroxidation; reactive oxygen species
  11. Clin Nutr ESPEN. 2021 Feb;pii: S2405-4577(20)31120-7. [Epub ahead of print]41 30-41
      BACKGROUND AND AIMS: A systematic review was conducted to assess the effects of glutamine, arginine and omega-3 supplementation on the tolerance to treatment, nutritional status and immune function of head and neck cancer (HNC) patients undergoing chemoradiotherapy.METHODS: Randomized clinical trials were searched in MEDLINE, EMBASE, CENTRAL, LILACS,, OpenGrey and Proquest. Tolerance to treatment, nutritional status, immune function and mortality rate were the primary outcomes investigated. Secondary outcomes comprised functional status, weight loss and body composition. Risk of bias of individual studies and the overall quality of the evidence were assessed using the Cochrane and the GRADE tools, respectively.
    RESULTS: Nineteen articles met the inclusion criteria and nine were included in the meta-analyses, which assessed mucositis severity, weight loss and handgrip strength. Ten studies were evaluated as high risk of bias. Glutamine supplementation has significantly reduced the risk of grade 2-4 mucositis (RR: 0.76, IC95% [0.63; 0.92], P = 0.006, I2 = 0%; P = 0.792; 4 studies). Omega-3 supplementation did not show statistically significant results on weight loss (SMD: -0.042, 95% CI [-0.322; 0.238], P = 0.769, I2 = 33.4%; P = 0.212; 4 studies). The overall quality of the evidence ranged from low to very low.
    CONCLUSIONS: These results must be interpreted with caution due to differences between supplementations regimen, lack of methodological rigor in most studies and due to the possible role of glutamine in tumor metabolism. Studies focused on elucidating the contribution of each immunonutrient to HNC patients undergoing chemoradiotherapy deserve further investigation.
    Keywords:  Arginine; Chemoradiotherapy; Fatty acids; Glutamine; Head and neck neoplasm; Immunomodulation; Omega-3
  12. Metabolomics. 2021 Jan 25. 17(2): 16
      INTRODUCTION: Chronic hepatitis B (CHB) affects 257 million individuals worldwide with an annual estimated mortality rate of 880,000 individuals. Accurate diagnosis of the stage of disease is difficult, and there is considerable uncertainty concerning the optimal point in time, when treatment should be started.OBJECTIVES: By analyzing and comparing the metabolomes of patients at different stages of CHB and comparing them to healthy individuals, we want to determine the metabolic signature of disease progression and develop a more accurate metabolome-based method for diagnosis of disease progression ultimately giving a better basis for treatment decisions.
    METHODS: In this study, we used the combination of transient elastography and serum metabolomics of 307 serum samples from a group of 90 patients with CHB before and under treatment (with a follow-up time up to 10 years) at different progression stages over the clinical phases and 43 healthy controls..
    RESULTS: Our data show that the metabolomics approach can successfully discover CHB changing from the immune tolerance to the immune clearance phase and show distinctive metabolomes from different medical treatment stages. Perturbations in ammonia detoxification, glutamine and glutamate metabolism, methionine metabolism, dysregulation of branched-chain amino acids, and the tricarboxylic acid (TCA) cycle are the main factors involved in the progression of the disease. Fluctuations increasing in aspartate, glutamate, glutamine, methionine and 13 other metabolites are fingerprints of progression.
    CONCLUSIONS: The metabolomics approach may expand the diagnostic armamentarium for patients with CHB. This method can provide a more detailed decision basis for starting medical treatment.
    Keywords:  Biomarker; Chronic hepatitis B; FibroScan; Liver fibrosis; Metabolomics; NMR
  13. Front Cell Dev Biol. 2020 ;8 614040
      Cell volume regulation (CVR) is essential for survival and functions of animal cells. Actually, normotonic cell shrinkage and swelling are coupled to apoptotic and necrotic cell death and thus called the apoptotic volume decrease (AVD) and the necrotic volume increase (NVI), respectively. A number of ubiquitously expressed anion and cation channels are involved not only in CVD but also in cell death induction. This series of review articles address the question how cell death is induced or protected with using ubiquitously expressed ion channels such as swelling-activated anion channels, acid-activated anion channels and several types of TRP cation channels including TRPM2 and TRPM7. The Part 1 focuses on the roles of the volume-sensitive outwardly rectifying anion channels (VSOR), also called the volume-regulated anion channel (VRAC), which is activated by cell swelling or reactive oxygen species (ROS) in a manner dependent on intracellular ATP. First we describe phenotypical properties, the molecular identity, and physical pore dimensions of VSOR/VRAC. Second, we highlight the roles of VSOR/VRAC in the release of organic signaling molecules, such as glutamate, glutathione, ATP and cGAMP, that play roles as double-edged swords in cell survival. Third, we discuss how VSOR/VRAC is involved in CVR and cell volume dysregulation as well as in the induction of or protection from apoptosis, necrosis and regulated necrosis under pathophysiological conditions.
    Keywords:  GSH release; VSOR/VRAC; apoptotic cell death; cell volume regulation; cisplatin resistance; glutamate release; necrotic cell death; programmed necrosis
  14. J Cell Commun Signal. 2021 Jan 28.
      Glutamine (gln) metabolism has emerged as a cancer therapeutic target in past few years, however, the effect of gln-deprivation of bCSCs remains elusive in breast cancer. In this study, effect of glutamine on stemness and differentiation potential of bCSCs isolated from MCF-7 and MDAMB-231 were studied. We have shown that bCSCs differentiate into CD24+ epithelial population under gln-deprivation and demonstrated increased expression of epithelial markers such as e-cadherin, claudin-1 and decreased expression of mesenchymal protein n-cadherin. MCF-7-bCSCs showed a decrease in EpCAMhigh population whereas MDAMB-231-bCSCs increased CD44high population in response to gln-deprivation. The expression of intracellular stem cell markers such sox-2, oct-4 and nanog showed a drastic decrease in gene expression under gln-deprived MDAMB-231-bCSCs. Finally, localization of β-catenin in MCF-7 and MDAMB-231 cells showed its accumulation in cytosol or perinuclear space reducing its efficiency to transcribe downstream genes. Conclusively, our study demonstrated that gln-deprivation induces differentiation of bCSCs into epithelial subtypes and also reduces stemness of bCSCs mediated by reduced nuclear localization of β-catenin. It also suggests that basal and luminal bCSCs respond differentially towards changes in extracellular and intracellular gln. This study could significantly affect the gln targeting regimen of breast cancer therapeutics.
    Keywords:  2‐Diazo‐norleucine (DON); Breast cancer stem cells; Epithelial mesenchymal transition; Glutamine; β-Catenin
  15. Front Pharmacol. 2020 ;11 582587
      Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors.
    Keywords:  L-asparaginase; amino acid degrading enzymes; arginine deiminase; autophagy; cancer therapy; chloroquine; recombinant human arginase
  16. Biochem Pharmacol. 2021 Jan 26. pii: S0006-2952(21)00023-X. [Epub ahead of print] 114427
      Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3β/ZBTB16 pathways in both Alzheimer's and Huntington's disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3β/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3β/ZBTB16 and mTOR/ULK-1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Autophagy; Ca(2+); GPCR; Optineurin; mGluR5