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Open accessJournal ArticleDOI: 10.3390/PH14030216

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine-Glycine-One-Carbon Pathways in Cancer.

04 Mar 2021-Pharmaceuticals, policy and law (Multidisciplinary Digital Publishing Institute)-Vol. 14, Iss: 3, pp 216
Abstract: The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.

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Topics: Methionine (62%), Amino acid (61%), Serine (60%) ... show more
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7 results found


Open accessJournal ArticleDOI: 10.3390/CANCERS13122900
Diren Beyoğlu1, Jeffrey R. Idle1Institutions (1)
10 Jun 2021-Cancers
Abstract: The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required.

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Topics: Cancer cell (52%), Epigenetics (51%), Histone demethylation (51%)

2 Citations


Open accessPosted ContentDOI: 10.1101/2021.06.01.446649
Le Guellec B1, Rousseau F1, Bied M1, Supplisson S1Institutions (1)
02 Jun 2021-bioRxiv
Abstract: GlyT2 (SLC6A5), two glycine-specific transporters coupled to 2:1 and 3:1 Na+:Cl-, respectively. However, ATB0,+ stoichiometry that specifies its driving force and electrogenicity remains unsettled. Using the reversal potential slope method, here we demonstrate that ATB0,+-mediated glycine transport is coupled to 3 Na+ and 1 Cl- and has a charge coupling of 2.1 e/glycine. ATB0,+ behaves as a unidirectional transporter with limited e and exchange capabilities. Analysis and computational modeling of the pre-steady-state charge movement reveal higher sodium affinity of the apo-ATB0,+, and a locking trap preventing Na+ loss at depolarized potentials. A 3 Na+/ 1 Cl- stoichiometry substantiates ATB0;+ concentrative-uptake and trophic role in cancers and rationalizes its structural proximity with GlyT2 despite their divergent substrate specificity. Analysis and computational modeling of the pre-steady-state charge movement reveal higher sodium affinity of the apo-ATB0,+, and a locking trap preventing Na+ loss at depolarized potentials. A 3 Na+/ 1 Cl- stoichiometry substantiates ATB0,+ concentrative-uptake and trophic role in cancers and rationalizes its structural proximity with GlyT2 despite their divergent substrate specificity.

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Topics: Glycine transport (60%)

1 Citations


Open accessJournal ArticleDOI: 10.1042/BCJ20210585
Abstract: Metabolic reprogramming in cancer necessitates increased amino acid uptake, which is accomplished by up-regulation of specific amino acid transporters. However, not all tumors rely on any single amino acid transporter for this purpose. Here, we report on the differential up-regulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The up-regulation is evident in TNBC tumors, conventional and patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous TNBC mammary tumor. The up-regulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since cell-surface Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to the induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger. Down-regulation of SLC38A5 in TNBC cells attenuates serine-induced macropinocytosis and reduces cell proliferation significantly as assessed by multiple methods, but does not induce cell death. The Cancer Genome Atlas database corroborates SLC38A5 up-regulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition and proliferation.

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Topics: Amino acid transporter (61%), Amino acid (54%), Cancer cell (51%)

Open accessJournal ArticleDOI: 10.3390/IJMS221910814
Abstract: Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

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Topics: Progenitor cell (53%), Hematopoietic stem cell (53%), Haematopoiesis (53%) ... show more

Open accessPosted ContentDOI: 10.1101/2021.06.17.448844
18 Jun 2021-bioRxiv
Abstract: Metabolic reprogramming in cancer cells necessitates increased amino acid uptake, which is accomplished by upregulation of specific amino acid transporters. Since amino acid transporters differ in substrate selectivity, mode of transport, and driving forces, not all tumors rely on any single amino acid transporter for this purpose. Here we report on the differential upregulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The upregulation is evident in primary TNBC tumors, conventional TNBC cell lines, patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous mammary tumor representing TNBC. The upregulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since the traditional Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger, possibly related to the amino acid-dependent Na+/H+ exchange function of SLC38A5. The Cancer Genome Atlas database corroborates SLC38A5 upregulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition. Summary Statement SLC38A5 is an amino acid-coupled Na+/H+ exchanger that is upregulated in triple-negative breast cancer, and its function in cancer cells goes beyond amino acid delivery; it promotes macropinocytosis, a distinct form of endocytic process for cellular uptake of proteins and other nutrients present in extracellular fluid.

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Topics: Amino acid transporter (63%), Amino acid (56.99%), Downregulation and upregulation (51%) ... show more

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96 results found


Open accessJournal ArticleDOI: 10.1073/PNAS.0709747104
Abstract: Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.

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Topics: Glutamine (65%), Glutaminolysis (62%), Citric acid cycle (59%) ... show more

1,957 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.0810199105
Abstract: Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.

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Topics: Glutaminolysis (65%), Glutamine (59%), Catabolism (53%) ... show more

1,511 Citations


Open accessJournal ArticleDOI: 10.1016/S0021-9258(17)30124-2
Larry Reitzer1, Burton M. Wice1, D Kennell1Institutions (1)
Abstract: Cultured HeLa cells grew at a similar rate when the sugar source was either glucose, galactose, or fructose. The relative rates of carbon flow through glycolysis and the pentose phosphate cycle, as well as total utilization, were a function both of the sugar and its concentration. When 21 mu, about 80% of the glucose carbon was metabolized through glycolysis to lactic acid, but only 4 to 5% of sugar carbon entered the citric acid cycle. At the other extreme, on 2 mu fructose about 100 times fewer molecules of fructose than glucose were used per new mass, and glycolytic activity was about 900 times lower with barely detectable levels of glycolytic intermediates in the cells. Almost all the fructose carbon passed through the pentose phosphate cycle with little or no energy derived from its metabolism. Since the cells continued to grow exponentially, we considered possible alternate sources of energy. Next to the sugar, glutamine is the most abundant carbon compound in culture media (2 111~). It was metabolized very rapidly in the presence of these sugars, e.g. 65 mol/mol of sugar on 2 mu fructose. Less than 2% was for direct incorporation into protein, and irrespective of the supporting sugar, 35% of glutamine carbon was incorporated into COz, 13% into lactate, and 18 to 25% into macromolecules. ATP levels did not change much as a function of sugar and were even maintained for some time in the absence of sugar, but only under aerobic conditions. Fairly constant intracellular levels of citric acid cycle intermediates were also maintained irrespective of the sugar, or in its absence, in contrast to the extremely variable levels of glycolytic intermediates. These observations suggest that glutamine provides energy by aerobic oxidation from citric acid cycle metabolism, provides more than half of the cell energy when high concentrations of glucose are present, and greater than 98% when fructose or galactose is the carbohydrate. The primary function of sugar in these cultures is probably to provide precursors for biosynthesis.

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Topics: Glutamine (62%), Energy source (59%), Carbohydrate metabolism (53%) ... show more

1,134 Citations


Open accessJournal ArticleDOI: 10.1093/BRAIN/AWQ386
Ralf A. Linker1, De-Hyung Lee1, Sarah Ryan, Anne M van Dam2  +14 moreInstitutions (3)
01 Mar 2011-Brain
Abstract: Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

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Topics: Experimental autoimmune encephalomyelitis (60%), Neuroprotection (54%), Neuroinflammation (54%) ... show more

802 Citations


Open accessJournal ArticleDOI: 10.1016/J.CMET.2016.08.009
10 Jan 2017-Cell Metabolism
Abstract: One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized. Here we review the fundamentals of mammalian 1C metabolism, including the pathways active in different compartments, cell types, and biological states. Emphasis is given to recent discoveries enabled by modern genetics, analytical chemistry, and isotope tracing. An emerging theme is the biological importance of mitochondrial 1C reactions, both for producing 1C units that are exported to the cytosol and for making additional products, including glycine and NADPH. Increased clarity regarding differential folate pathway usage in cancer, stem cells, development, and adult physiology is reviewed and highlights new opportunities for selective therapeutic intervention.

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Topics: Amino acid homeostasis (56.99%), Serine (52%)

708 Citations


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