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Glutamine and metabolism

Glutamine and metabolism

Article Glutamone CAS Google Scholar Selak, M. Rho Metaboism regulates Glutamine and metabolism metabolism in a nuclear factor-kappa B NF-κB -dependent manner. Article CAS PubMed PubMed Central Google Scholar Hettmer, S. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Dutchak, P. Cancer —

Glutamine and metabolism -

In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis.

To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism s involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment.

Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms.

Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.

Metabolic reprogramming, a hallmark of cancer cells, is a process by which cancer cells ensure a sufficient supply of proteins, nucleotides, and lipids to support rapid growth and proliferation 1. The importance of cancer cell metabolism and the limitations of conventional cancer therapies e.

Several drugs that do just that have been introduced and have shown promising results in animal studies; a few have entered clinical trials 2. In particular, glutamine metabolism has attracted much attention as a therapeutic target because cancer cells are heavily reliant on this amino acid for growth and proliferation 3.

Glutamine metabolism and closely linked metabolic networks involving glutamine transporters, glutaminase, aminotransferase, and redox homeostasis are essential for cancer cell survival 6. Targeting each step of glutamine metabolism has shown promising results in cancer treatment, prompting the discovery of druggable targets and the development of anticancer drug candidates 3.

In addition, given that immune checkpoint inhibitors are now widely used to treat cancer, the role of glutamine blockade within the tumor microenvironment TME has gained much attention 7.

This review summarizes each step of glutamine metabolism in cancer cells and highlights opportunities for clinical intervention. Furthermore, we discuss resistance mechanisms and the role of glutamine blockade in the TME.

Rapidly proliferating cancer cells take up glutamine from plasma via various amino acid transporters, and then it is converted to glutamate in the mitochondria by the two forms of glutaminase: kidney-type glutaminase GLS 1 and liver-type GLS2 8. Notably, GLS-mediated deamination of glutamine to glutamate is the first and rate-limiting step of glutaminolysis, making it an attractive druggable target 9.

GLS1 is overexpressed in various cancer cells, and this phenotype is associated with a higher disease stage and a poor prognosis Mechanistically, the expression of GLS1 is regulated indirectly by Myc via repression of miRa and miRb and mTORC1 11 , Unlike GLS1, GLS2 suppresses the proliferation and migration of cancer cells In hepatocellular carcinoma HCC , GLS2 inhibited proliferation in vitro and lung metastasis in a xenograft mouse model by inhibiting the small GTPase Rac1 However, several studies have shown that GLS2 is highly expressed in triple-negative basal-like breast cancer TNBC and metastatic lung cancer and that it confers radioresistance in advanced human cervical cancer cells, suggesting that GLS2 may reduce reactive oxygen species ROS levels by increasing the level of cellular reduced glutathione GSH , NADH, or NADPH 14 , 15 , The confounding results regarding the function of GLS2 in cancer metabolism suggest that it may act in a context-specific manner The TCA cycle is an essential hub for several metabolic pathways and for the interconversion of metabolites, which are renewed constantly in rapidly proliferating cancer cells Thus, replenishment of metabolic intermediates via the TCA cycle is vital to cancer cells, making them reliant on glutamine, a phenomenon called anaplerosis 8.

During anaplerosis, mitochondrial glutamate dehydrogenase 1 GLUD1 plays a key role by catalyzing the conversion of glutamate to alpha-ketoglutarate α-KG and releasing ammonia, which regulates autophagy and neutralizes the intracellular pH in cancer cells 19 , α-KG is generated for the TCA cycle and is used for oxidative phosphorylation OXPHOS In addition, glutamine-derived α-KG is oxidized to succinate and fumarate, which maintain the TCA cycle in cancer cells by providing ATP, NADH, and FADH 2 and by acting as oncometabolites Indeed, GLUD1 is overexpressed in various cancer cells, promoting epithelial-mesenchymal transition and drug resistance Mechanistically, Myc drives glutaminolysis by upregulating GLUD1 and induces a concurrent increase in the expression of GLS and SLC1A5 Amino acids are required by cancer cells for proliferation under genotoxic, oxidative, and nutritional stress conditions; these amino acids serve as building blocks for protein synthesis and act as substrates for glucose, lipid, and nucleic acid synthesis 25 , In particular, glutamine plays a vital role in this process not only by providing a carbon source to the TCA cycle but also by acting as a nitrogen source for the biosynthesis of alanine, aspartate, and serine Fig.

Therefore, the role of aminotransferases such as glutamate pyruvate transaminase GPT and glutamate oxaloacetate transaminase GOT in glutamine metabolism in cancer cells has been studied extensively 8.

Regarding GPTs, cytosolic GPT1 and mitochondrial GPT2 play major roles in energy metabolism in cancer cells by providing alanine for protein synthesis and by replenishing TCA cycle intermediates Indeed, GPT2 is a significant contributor to tumorigenesis in breast cancer, glioblastoma, and KRAS-driven colorectal cancer CRC cells 28 , 29 , 30 , Because cancer cells do not take up aspartate very well, GOT fuels tumorigenesis by providing cytosolic aspartate, which is used as a precursor for protein and nucleotide synthesis and for redox homeostasis Cytosolic GOT1 and mitochondrial GOT2, which together comprise the malate-aspartate shuttle, interconvert oxaloacetate and aspartate using glutamate or α-KG as substrates Indeed, both GOT1 and GOT2 are overexpressed in KRAS-driven pancreatic ductal adenocarcinoma PDAC cells 34 , Glutamine is also required for de novo synthesis of asparagine via asparagine synthetase ASNS , which is induced by either the amino acid response or the unfolded protein response pathways 36 , Asparagine activates mTORC1 and contributes to the biosynthesis of purines and pyrimidines, as well as to the exchange of extracellular amino acids such as histidine, aspartate, and serine Indeed, the role of ASNS in tumorigenesis and metastasis has been reported, and it is associated with poor survival in various types of breast cancer, non-small cell lung cancer NSCLC , and sarcoma 38 , 39 , Next, the SLC1A5 variant transports glutamine to the mitochondrial matrix, where it is converted to glutamate by GLS; this is the rate-limiting step of glutaminolysis.

Glutamine-derived glutamate is catalyzed into α-KG by GLUD1, GOT2, and GPT2 to release ammonia, aspartate, and alanine, respectively.

GOT1, which is part of the malate-aspartate shuttle, contributes to the maintenance of redox homeostasis by converting OAA to aspartate, and GPT1 converts pyruvate to alanine.

SLC7A11 transports cysteine to the cytosol in exchange for glutamate. Inhibitors of each step of glutamine metabolism are shown in white boxes.

GLS, glutaminase; α-KG, α-ketoglutarate; GLUD1, glutamate dehydrogenase 1; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; GCLM, glutamate-cysteine ligase modifier subunit; GCLC, glutamate-cysteine ligase catalytic subunit; GSS, glutathione synthetase; GSH, reduced glutathione; ROS, reactive oxygen species; ASNS, asparagine synthetase; PSAT1, phosphoserine aminotransferase 1.

GLS, which is highly expressed in cancer cells and plays a role in cancer progression, has been investigated extensively as a druggable target Bis 5-phenylacetamido-1,2,4-thiadiazolyl ethyl BPTES , a potent orally available GLS1 inhibitor that spares GLS2, shows promising antitumor effects against human lymphoma B cells in vitro and in a xenograft mouse model 42 ; it also suppresses the growth of platinum-resistant CRC and ovarian cancer cells, suggesting that combined treatments based on conventional drugs and glutamine-modulating compounds will yield clinically relevant results 43 , Recently, another selective inhibitor of GLS1, CB telaglenastat , showed no significant side effects in preclinical trials and is currently undergoing full clinical trials Previous studies showed that it did not significantly suppress the growth of KRAS-derived PDAC cells in vitro or in vivo because these cells mounted an adaptive metabolomic response, suggesting the importance of combined therapy for avoiding metabolic adaptation in response to GLS inhibition Thus, clinical trials are currently testing the following drugs in combination with CB nivolumab as a treatment for melanoma, renal cell carcinoma RCC , and NSCLC clinicaltrials.

gov ID: NCT ; everolimus for RCC clinicaltrials. gov ID: NCT ; palbociclib for KRAS-derived PDAC, NSCLC and CRC clinicaltrials. gov ID: NCT ; and cabozantinib for advanced RCC clinicaltrials. gov ID: NCT Furthermore, CB increased the radiosensitivity of head and neck squamous carcinoma HNSCC and NSCLC cells both in vitro and in a xenograft mouse model by abolishing GSH synthesis 47 , 48 , making it useful for concurrent chemotherapy and radiotherapy in a clinical setting.

Previous studies have shown that targeting GLUD1 inhibits the proliferation and migration of cancer cells, suggesting that GLUD1 is a druggable target for cancer therapy Epigallocatechin gallate EGCG , an inhibitor of GLUD1 and 2, suppresses the proliferation of neuroblastoma, glioma, and CRC cells Recently, the purpurin analog R an inhibitor of GLUD1 also showed promising results with respect to attenuating the proliferation of breast, NSCLC, and glioma cells in vitro and in patient-derived xenograft mouse models In addition, cotreatment of docetaxel-resistant NSCLC with docetaxel plus R inhibited cancer cell growth and metastasis both in vitro and in xenograft mouse models, again suggesting that combination therapy with anticancer drugs plus a GLUD1 inhibitor is an effective cancer treatment ROS levels are elevated persistently in proliferating cancer cells, and ROS damage DNA and cellular components; therefore, redox homeostasis plays a pivotal role in protecting cancer cells against them.

Notably, GSH acts as a critical antioxidant that protects cancer cells from any form of programmed cell death i. Given that glutathione is a tripeptide composed of glutamate, glycine, and cysteine, glutamine-derived glutamate and cysteine need to be ligated by glutamate-cysteine ligase GCL , which itself comprises two separately encoded proteins: a catalytic subunit GCLC and a modifier subunit GCLM 53 , Next, glutathione synthetase GSS adds glycine to the ligated glutamate-cysteine Fig.

While glutamate and glycine are abundant in cells, cysteine is the least abundant amino acid; therefore, it must be transported into the cells by SLC7A11 xCT in exchange for glutamate, which implies that SLC7Amediated GSH biosynthesis largely relies on glutamine metabolism In addition, we previously showed that upon inhibition of glutamine, cancer cells reduce the amount of GSH by exporting oxidized glutathione GSSG out of the cell via GSSG transporters and multiple-drug resistance-associated proteins 57 and by extracellular degradation of GSSG Approximately one-third of glutamine taken up by human fibroblast cells is exchanged for cysteine by SLC7A11 59 , This suggests that SLC7A11 not only plays a critical role in protein and GSH synthesis through cysteine uptake but also dictates glutamine dependence Therefore, targeting SLC7A11 is a promising therapeutic option, and its efficacy can be increased by combining it with drugs that target glutaminolysis Indeed, sulfasalazine which inhibits SLC7A11 effectively suppresses the proliferation of glutamine-depleted TNBC in vitro and in vivo Moreover, glutamine-dependent PDAC is sensitive to the SLC7A11 inhibitor erastin, which induces ferroptosis 62 , However, although erastin shows antitumor effects, it has not entered clinical trials because it is poorly soluble in water, and its metabolism in vivo is unpredictable; therefore, imidazole ketone erastin IKE and piperazine erastin were developed which are more soluble in water , and both show strong antitumor effects against diffuse large B-cell lymphoma DLBCL and fibrosarcoma 64 , Intriguingly, and as mentioned above, PDAC cells are dependent on GOT1 and the malate-aspartate shuttle; GOT1 knockout combined with cysteine depletion by erastin or IKE showed potent antitumor effects against these cells by reducing GSH and increasing ferroptosis In addition, sorafenib, a kinase inhibitor approved for the treatment of RCC and HCC, inhibits SLC7A11 to suppress the growth of these tumors via the induction of ferroptosis 67 , Cancer cells require an abundant supply of glutamine from the extracellular milieu; therefore, upregulation of glutamine transporters SLC1A5, SLC38A1, SLC38A2, and SLC6A14 at the cell membrane is required Fig.

Indeed, high expression of these transporters contributes to cancer cell growth and is a marker of clinically poor outcomes for patients with NSCLC, prostate cancer, breast cancer, and acute myeloid leukemia 70 , 71 , 72 , Thus, cancer treatment strategies have focused on pharmacological inhibition of these transporters.

SLC1A5 ASCT2 is an obligatory sodium-dependent transporter of neutral amino acids, which are exchanged for asparagine, threonine, or serine SLC1A5 has high affinity for glutamine, particularly in an acidic environment 75 , and is thus more effective at transporting glutamine into cancer cells that thrive in acidic environments The expression of SLC1A5 is regulated by various transcriptional regulators, including ATF4 and Myc 78 , In TNBC, high expression of ATF4 and Myc is associated with overexpression of SLC1A5 and indicates poor survival outcomes In addition, Myc-dependent expression of ATF4 in DLBCL cells, human colon adenocarcinoma cells, and mouse embryonic fibroblasts drives the expression of SLC1A5 during metabolic adaptation to stress conditions 73 , 80 , A recent study showed that HIF-2α-mediated overexpression of SLC1A5 variants in mitochondria plays an essential role in glutamine metabolism in pancreatic cancer cells by inducing chemotherapy resistance Therefore, SLC1A5 is a promising druggable target Benzylserine and benzylcysteine were the first molecules found to inhibit SLC1A5 in breast and gastric cancer cells, but they are nonspecific 84 , L-γ-glutamyl-p-nitroanilide GPNA suppresses the growth of TNBC, different types of lung cancer, and neuroblastoma cells 73 , 77 , In addition, combined treatment with GPNA and a monoclonal antibody cetuximab targeting EGFR effectively suppressed the growth of gastric cancer cells in vitro and in vivo However, amino acid analogs are unsuitable for clinical use due to their low affinity, lack of specificity, and toxicity V 2-aminobis aryloxy benzyl aminobutanoic acid was originally discovered as an SLC1A5 inhibitor; it showed a fold increase in potency over GPNA and attenuated the growth of cancer cells, including HCC, CRC, lung cancer, and breast cancer cells Recent studies have shown that synthetic monoclonal antibodies specific for SLC1A5 i.

Despite the significance of SLC1A5 in some cancer cells, there are few specific and effective SLC1A5-inhibiting drugs SLC38A1 SNAT1 and SLC38A2 SNAT2 are sodium-dependent neutral amino acid transporters that drive glutamine influx into cells SLC38A1 is overexpressed in melanoma, breast, gastric, osteosarcoma, and endometrial cancer cells, showing a close association with proliferation and migration 91 , 92 , SLC38A2 is highly expressed in prostate cancer, HCC, and TNBC cells, thereby contributing to tumorigenesis 94 , Interestingly, silencing of SLC1A5 does not suppress the proliferation of epithelial cervical cancer and osteosarcoma cells; rather, it induces an amino acid starvation response by upregulating the expression of SLC38A1, suggesting that SLC38A1 is a major importer of glutamine into these cells In addition, amino acid starvation upregulates SLC38A2 via activation of GCN2 and ATF4, which help to maintain the intracellular glutamine pool 36 , Therefore, strategies designed to target glutamine metabolism should consider the combined blockade of these transporters.

Recently, it was proposed that the aforementioned drug V targets SLC38A2 and SLC7A5 rather than SLC1A5 A previous study supported this, showing that treatment of SLC1A5 -knockdown HNSCC cell lines with V led to marked inhibition of glutamine metabolism, thereby suppressing growth and proliferation both in vitro and in vivo Therefore, combination therapy with V and SLC1A5-specific inhibitors may be a promising therapeutic option for some cancers Given the functional role of SLC6A14 in extending the range of amino acid uptake including glutamine and leucine, both of which are activators of mTORC1 , as well as providing substrates for SLC1A5 and SLC7A5, the molecule has attracted much attention 99 , Indeed, SLC6A14 is overexpressed in colon, cervical, ER-positive breast, and pancreatic cancer cells and is associated with their proliferation , , , High expression of SLC6A14 in PDAC and CRC cells is closely associated with metastasis and a poor outcome , , Mechanistically, SLC6A14 expression is regulated by the Wnt signaling pathway, and genetic or pharmacological inhibition of the transporter and its downstream effectors suppresses the growth of CRC cells both in vitro and in vivo Given that tryptophan is a substrate for SLC6A14, the inhibitor α-methyltryptophan α-MT suppresses the growth of SLC6Apositive breast cancer, PDAC, and CRC cells but not SLC6Anegative cells , , Combined treatment of pancreatic cancer cells with gemcitabine and α-MT significantly inhibited proliferation and migration Although the role of SLC6A14 in cancer cells is becoming clearer, few compounds targeting SLC6A14 have been developed; thus, an effective drug targeting this transporter needs to be developed.

Although targeting glutamine metabolism is a promising therapeutic approach, few drugs have been developed. Tumor metabolism is affected by a multitude of microenvironmental factors, including nutrient availability. There are several mechanisms by which cancer cells escape the effects of inhibitors of glutamine metabolism; these include increased metabolic flexibility, uptake of extracellular amino acids via compensatory transporters and macropinocytosis, and expression of nutrient stress-response proteins Fig.

a Glutamine starvation induces metabolic flexibility, in which the influx of glucose-derived pyruvate via MPC and fatty acid-derived acyl-CoA via CPT1 into the mitochondria drives TCA cycle activity. b Under conditions of glutamine deprivation, the tumor suppressor protein p53 induces the expression of the SLC1A3 and SLC7A2 transporters.

Aspartate uptake through SLC1A3 transporters increases the amount of malate, which is a TCA cycle intermediate, leading to an increase in oxidative phosphorylation and glutamine synthesis. Aspartate is used for nucleotide synthesis.

Arginine uptake through SLC7A3 transporters restores mTORC1 expression, which is suppressed by glutamine depletion. The high level of intracellular asparagine increases the expression of GLUL proteins, thereby increasing glutamine and protein synthesis. c Under conditions of nutrient stress, macropinocytosis internalizes extracellular macromolecules to supply amino acids.

Membrane ruffling aids in the uptake of extracellular macromolecules, such as serum albumin, via the formation of macropinosomes.

After fusion between macropinosomes and lysosomes, albumin is degraded to supply amino acids to the cytosol and the mitochondrial TCA cycle.

Although glutamine is the primary carbon source for the TCA cycle in some cancer cells, replenishment of TCA cycle intermediates using alternative anaplerotic substrates reduces bioenergetic stress, thereby enabling resistance to inhibition of glutamine metabolism.

There are two main anaplerotic flux pathways that feed the citric acid cycle: glutamine flux via glutaminase and glucose flux via pyruvate carboxylase Upon interruption of glutamine metabolism, glutamine-addicted tumor cells employ compensatory anaplerotic mechanisms via pyruvate carboxylase, which generates the oxaloacetate required to maintain TCA cycle flux; thus, the levels of pyruvate carboxylase can greatly affect the sensitivity of tumor cells to inhibition of glutamine metabolism In addition, deletion of GLS1 genes from Myc-driven liver tumors upregulates several metabolic compensatory pathways, including glycolysis and aminotransferases Thus, combined inhibition of glycolytic genes encoding hexokinase II or aminotransferases increases the efficacy of the GLS1 inhibitor CB In contrast, CB showed no antitumor activity in PDAC mouse models due to the use of alternative metabolic pathways e.

Integrated metabolomics and proteomics platforms revealed a marked increase in fatty acid oxidation-related metabolites, as well as proteome changes, in PDAC treated with GLS1 inhibitors, suggesting that treatments should target multiple metabolic pathways to overcome metabolic plasticity , Amino acids, including aspartate, arginine, and asparagine, are associated with resistance to glutamine depletion.

Increases in the levels of intracellular aspartate via SLC1A3 contribute to nucleotide synthesis and maintain the electron transport chain and TCA cycle Although the uptake of arginine by SLC7A3 transporters does not maintain TCA cycle flux under conditions of glutamine depletion, arginine activates mTORC1 and contributes to metabolic adaptation and tumor growth Uptake of extracellular asparagine prevents the death of glioblastoma cells in response to glutamine depletion by blocking the apoptotic function of a glutamine-induced endoplasmic reticulum stress marker protein, ATF4, and by increasing glutamate-ammonia ligase GLUL -mediated glutamine and protein synthesis , Thus, blocking amino acid transporters or depleting amino acids such as L-asparaginase may be effective therapeutic strategies to overcome resistance to glutamine withdrawal.

Macropinocytosis, a nutrient-scavenging pathway, is a compensatory route that supplies amino acids to nutrient-starved cancer cells harboring oncogenic mutations in KRAS or PTEN , , Experiments using isotope-labeled extracellular proteins show that when supplied with extracellular serum albumin, Ras-transformed cells, which rely on glutamine metabolism to support growth, utilize macropinocytosis to maintain proliferation under glutamine-limiting conditions Macropinocytosis also facilitates the survival of hypoxic HCC cells.

Thus, HCC cells can internalize extracellular proteins by increasing the expression of a membrane ruffling protein called EH domain-containing protein 2, leading to resistance to glutamine deprivation under hypoxic conditions Although targeting macropinocytosis could be a key strategy for overcoming resistance to glutamine uptake blockade, further studies are necessary to examine whether macropinocytosis can overcome tumor cell resistance to glutamine antimetabolites or GLS inhibitors that target enzymes involved directly in glutamine metabolism.

Limiting glutamine utilization regulates nutrient stress-response proteins and transcription factors. Sestrin2-mediated suppression of mTORC1 and mTORC2 activation reprograms lipid metabolism to limit ATP and NADPH consumption, thereby enabling cancer cells to survive under glutamine-depleted conditions.

Other studies have shown that ROS production in response to glutamine deprivation increases the expression of pdependent genes Gadd45a, Cdkn1, and Sestrin2 via B55α or IKKβ , Upregulation of Gadd45a and Cdkn1 induces cell cycle arrest in response to glutamine deprivation, which alleviates oxidative stress and reduces energy consumption , The TME is a complex milieu that surrounds tumor cells, often providing immunosuppressive cover that facilitates immune invasion.

Specifically, competition for nutrients or cell-intrinsic programming between cancer cells and immune cells induces nutrient deficiency and metabolic reprogramming of immune cells, leading to modulation of antitumor immunity , Given that activation and differentiation of immune cells are coupled to metabolic reprogramming, regulating the metabolic activity of immune cells should be considered in the development of potential strategies that target glutamine metabolism , Accumulating evidence shows that glutamine is an immunomodulatory nutrient in immune cells.

Naïve T cells are metabolically quiescent, undergoing basal levels of glycolysis and glutaminolysis sufficient to maintain minimal biosynthesis; however, T-cell receptor TCR -stimulated activation increases the expression of the Myc transcription factor, glutamine transporters SLC38A1, SLC38A2 , and glutaminolysis-related enzymes GLS, GLUD1, GOT, GPT to meet bioenergetic and biosynthetic requirements, resulting in T-cell proliferation , , , Mechanistically, α-KG decreases Treg differentiation by inhibiting FOXP3 and upregulating inflammatory cytokines such as IFN-γ, Tbet, and Rorc, suggesting that Th1-type effector T cells are more dependent on glutaminolysis than Treg cells Moreover, effector T cells are capable of adapting their metabolism in response to nutrient limitation.

Activated T cells rely on glutamine-dependent OXPHOS to maintain energetic homeostasis under energy-related stress e. Although amino acids are essential for the function of NK cells, their main role in NK cells is the maintenance of signaling e. Unlike other lymphocyte subsets, glutaminolysis and the TCA cycle do not sustain OXPHOS in activated NK cells.

Glutamine withdrawal, but not inhibition of glutaminolysis, results in loss of c-Myc protein, reduced cell growth, and impaired NK cell responses Consistent with this, receptor-simulated production of IFN-γ by NK cells is not impaired under glutamine-limited conditions In macrophages, glutamine metabolism is a critical metabolic pathway for differentiation.

Macrophages undergo metabolic switching during differentiation into inflammatory M1 or anti-inflammatory M2 phenotypes. Tumor-associated macrophages TAMs can exhibit either an antitumor M1-like phenotype or a protumor M2-like phenotype. Glutamine starvation inhibits M2 polarization but not M1 polarization by suppressing UDP-GlcNAc biosynthesis and N-glycosylation of M2-related proteins such as Relmα, CD, and CD Consistent with this, glutaminolysis-derived α-KG promotes M2 activation by increasing fatty acid oxidation and Jmjd3-dependent epigenetic reprogramming of M2-related genes In contrast to the inhibition of glutaminolysis, pharmacological or genetic targeting of GLUL in macrophages reprograms M2-polarized macrophages to an M1-polarized phenotype Mechanistically, macrophage-specific inhibition of GLUL leads to accumulation of succinate and HIF-1α via glutamine-dependent γ-aminobutyric acid GABA shunting thereby inhibiting vessel sprouting and metastasis and via stimulation of T effector cells; however, ILinduced expression of GLUL promotes vessel sprouting, immunosuppression, and metastasis Given the importance of glutamine metabolism to immune cells, including activated lymphocytes, it is crucial to determine whether blockade of glutamine metabolism in tumor cells hampers anticancer immune responses; the answer may be key to the success of therapeutic strategies targeting glutamine metabolism.

The metabolism of cancer cells and immune cells in the TME is regulated by cell-intrinsic programs through mTORC1 signaling PET tracers showed that cancer cells rely heavily on glutamine uptake via mTORC1 signaling, while myeloid cells in the TME are more dependent on glucose, as are T cells and cancer cells but to a lesser extent Accumulating evidence shows that inhibitors of glutamine metabolism, such as V, JHU, and CB, elicit stronger antitumor effects when used in combination with immune checkpoint inhibitors , , Fig.

In a previous study, we showed that V induces the expression of PD-L1 by tumor cells and augments immune evasion in synergistic murine models Therefore, agents that target glutamine utilization may, when used in combination with an anti-PD-L1 antibody, boost antitumor immunity Similar results were reported for several tumors , , , Furthermore, bladder tumors in mice supplemented with glutamine showed lower PD-L1 levels than control tumors As a therapeutic option, combined treatment with asparaginase and an anti-PD-1 antibody could be useful because glutamine-addicted cells are sensitive to asparaginase PD-L1 suppresses antitumor immune responses by blocking T-cell activation in the tumor microenvironment.

b Treatment with glutamine analogs, including DON and JHU, decreases glucose and glutamine metabolism, leading to inhibition of tumor growth via a decrease in hypoxia, acidosis, and nutrient depletion in the tumor microenvironment.

Furthermore, DON decreases the recruitment of MDSCs by suppressing the secretion of CSF3 by tumor cells and blocking the production of the immunosuppressive metabolite kynurenine; this inhibits the synthesis of the hyaluronan-rich ECM, resulting in the activation and infiltration of T cells.

PD-L1, programmed death-ligand 1; CSF3, colony stimulating factor 3; MDSC, myeloid-derived suppressor cell; ECM, extracellular matrix. Another study showed that in JHUtreated cancer cell allograft models, an increase in nutrient levels and oxygen and a decrease in the acidity of the TME resulted in T-cell-mediated tumor suppression , whereas another study demonstrated the effects of JHU on myeloid-derived suppressor cells MDSCs and TAMs Glutamine metabolism plays a central role in regulating uncontrolled tumor growth by modulating bioenergetic and redox homeostasis and by serving as a precursor for the synthesis of biomass.

Although targeting glutamine metabolism is a promising strategy for cancer therapy, there are many hurdles to be overcome before we develop a clinically effective drug.

Metabolic flexibility or adaptation by cancer cells, as well as reduced antitumor immunity, may be unwanted consequences of inhibiting glutamine metabolism. A comprehensive understanding of the TME is of the utmost importance because it provides valuable insights into pathways that could be targeted by novel metabolic therapies for advanced or drug-resistant cancers.

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Scalise, M. Cysteine of the ASCT2 amino acid transporter is a molecular determinant of the antiport mechanism. Sastrasinh, M. Effect of acute pH change on mitochondrial glutamine transport. Some societies use Oxford Academic personal accounts to provide access to their members.

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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Journal Article. Glutamine Metabolism, Sensing and Signaling in Plants Get access. Kim-Teng Lee , Kim-Teng Lee.

Institute of Plant and Microbial Biology, Academia Sinica. Molecular and Biological Agricultural Sciences, The Taiwan International Graduate Program, Academia Sinica. Oxford Academic. Google Scholar.

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Abstract Glutamine Gln is the first amino acid synthesized in nitrogen N assimilation in plants. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals. permissions oup.

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Thank you for visiting nature. You are using a browser version with limited Glutamine and metabolism for CSS. Netabolism CLA and hormonal imbalances the best experience, we recommend Cognitive training for endurance sports use a metabklism up anc date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis.


Inhibition of Glutamine Metabolism: Acting on Tumoral Cells or Tumor Microenvironment? - Oncotarget Glutamine Glutsmine is the first ajd acid synthesized in nitrogen N assimilation in plants. Plants have metabooism GS isoenzymes that work Metabolism Boosting Supplements Astaxanthin and sun protection cooperatively Glutamine and metabolism mtabolism that ketabolism Gln supply is sufficient for plant growth and development under various conditions. Gln is a building block for protein synthesis and an N-donor for the biosynthesis of amino acids, nucleic acids, amino sugars and vitamin B coenzymes. Most reactions using Gln as an N-donor are catalyzed by Gln amidotransferase GAT that hydrolyzes Gln to Glu and transfers the amido group of Gln to an acceptor substrate. Several GAT domain—containing proteins of unknown function in the reference plant Arabidopsis thaliana suggest that some metabolic fates of Gln have yet to be identified in plants. Glutamine and metabolism

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