A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells

Altman, 2016, From Krebs to clinic: glutamine metabolism to cancer therapy, Nat. Rev. Cancer, 16, 619, 10.1038/nrc.2016.71 Bothwell, 2018, Targeted suppression and knockout of ASCT2 or LAT1 in epithelial and mesenchymal human liver cancer cells fail to inhibit growth, Int. J. Mol. Sci., 19, E2093, 10.3390/ijms19072093 Bröer, 2018, Disruption of Amino Acid Homeostasis by Novel ASCT2 Inhibitors Involves Multiple Targets, Front. Pharmacol., 9, 785, 10.3389/fphar.2018.00785 Bröer, 2019, Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells, J. Biol. Chem., 294, 4012, 10.1074/jbc.RA118.006378 Burnham-Marusich, 2012, Multiple proteins with essential mitochondrial functions have glycosylated isoforms, Mitochondrion, 12, 423, 10.1016/j.mito.2012.04.004 Cassago, 2012, Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism, Proc. Natl. Acad. Sci. USA, 109, 1092, 10.1073/pnas.1112495109 Chacinska, 2009, Importing mitochondrial proteins: machineries and mechanisms, Cell, 138, 628, 10.1016/j.cell.2009.08.005 Chen, 2016, Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism, Cell, 166, 1324, 10.1016/j.cell.2016.07.040 Chen, 2017, Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer, Sci. Rep., 7, 7950, 10.1038/s41598-017-08436-6 Cho, 2016, On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models, Nature, 539, 107, 10.1038/nature19795 Davidson, 2004, An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines, Cancer Res., 64, 3761, 10.1158/0008-5472.CAN-03-3363 DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab., 7, 11, 10.1016/j.cmet.2007.10.002 Durán, 2012, Glutaminolysis activates Rag-mTORC1 signaling, Mol. Cell, 47, 349, 10.1016/j.molcel.2012.05.043 Fan, 2013, Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia, Mol. Syst. Biol., 9, 712, 10.1038/msb.2013.65 Hassanein, 2013, SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival, Clin. Cancer Res., 19, 560, 10.1158/1078-0432.CCR-12-2334 Hedley, 1994, Evaluation of methods for measuring cellular glutathione content using flow cytometry, Cytometry, 15, 349, 10.1002/cyto.990150411 Helenius, 2001, Intracellular functions of N-linked glycans, Science, 291, 2364, 10.1126/science.291.5512.2364 Hovius, 1990, Improved methods to isolate and subfractionate rat liver mitochondria. Lipid composition of the inner and outer membrane, Biochim. Biophys. Acta, 1021, 217, 10.1016/0005-2736(90)90036-N Hu, 2009, Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose, J. Biol. Chem., 284, 547, 10.1074/jbc.M808518200 Indiveri, 1998, Identification and purification of the reconstitutively active glutamine carrier from rat kidney mitochondria, Biochem. J., 333, 285, 10.1042/bj3330285 Karbowski, 2006, Role of Bax and Bak in mitochondrial morphogenesis, Nature, 443, 658, 10.1038/nature05111 Kekuda, 1996, Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line, J. Biol. Chem., 271, 18657, 10.1074/jbc.271.31.18657 Kondo, 2002, Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein, Cancer Cell, 1, 237, 10.1016/S1535-6108(02)00043-0 Kung, 2009, Global analysis of the glycoproteome in Saccharomyces cerevisiae reveals new roles for protein glycosylation in eukaryotes, Mol. Syst. Biol., 5, 308, 10.1038/msb.2009.64 Le, 2012, Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells, Cell Metab., 15, 110, 10.1016/j.cmet.2011.12.009 Li, 2019, Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway, EBioMedicine, 39, 239, 10.1016/j.ebiom.2018.11.063 Liu, 2017, Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens, Nat. Protoc., 12, 439, 10.1038/nprot.2016.174 Liu, 2018, The role of ASCT2 in cancer: A review, Eur. J. Pharmacol., 837, 81, 10.1016/j.ejphar.2018.07.007 Lukey, 2019, Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer, Cell reports, 29, 76, 10.1016/j.celrep.2019.08.076 Matés, 2009, Glutamine homeostasis and mitochondrial dynamics, Int. J. Biochem. Cell Biol., 41, 2051, 10.1016/j.biocel.2009.03.003 Metallo, 2011, Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia, Nature, 481, 380, 10.1038/nature10602 Molina, 1995, Glutamine transport by vesicles isolated from tumour-cell mitochondrial inner membrane, Biochem. J., 308, 629, 10.1042/bj3080629 Nicklin, 2009, Bidirectional transport of amino acids regulates mTOR and autophagy, Cell, 136, 521, 10.1016/j.cell.2008.11.044 Ouyang, 2000, Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype, Am. J. Pathol., 157, 1623, 10.1016/S0002-9440(10)64800-6 Pavlova, 2018, As extracellular glutamine levels decline, asparagine becomes an essential amino acid, Cell Metab., 27, 428, 10.1016/j.cmet.2017.12.006 Pochini, 2014, Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health, Front Chem., 2, 61, 10.3389/fchem.2014.00061 Sanjana, 2014, Improved vectors and genome-wide libraries for CRISPR screening, Nat. Methods, 11, 783, 10.1038/nmeth.3047 Sappington, 2016, Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines, Biochim. Biophys. Acta, 1860, 836, 10.1016/j.bbagen.2016.01.021 Schulte, 2016, 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport, Bioorg. Med. Chem. Lett., 26, 1044, 10.1016/j.bmcl.2015.12.031 Schulte, 2018, Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models, Nat. Med., 24, 194, 10.1038/nm.4464 Semenza, 1996, Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1, J. Biol. Chem., 271, 32529, 10.1074/jbc.271.51.32529 Shukla, 2017, MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer, Cancer Cell, 32, 392, 10.1016/j.ccell.2017.08.008 Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature, 496, 101, 10.1038/nature12040 Tkacz, 1975, Tunicamycin inhibition of polyisoprenyl N-acetylglucosaminyl pyrophosphate formation in calf-liver microsomes, Biochem. Biophys. Res. Commun., 65, 248, 10.1016/S0006-291X(75)80086-6 Velletri, 2013, GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation, Cell Cycle, 12, 3564, 10.4161/cc.26771 Wang, 2015, Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1, Science, 347, 188, 10.1126/science.1257132 Wieckowski, 2009, Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells, Nat. Protoc., 4, 1582, 10.1038/nprot.2009.151 Willems, 2013, Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia, Blood, 122, 3521, 10.1182/blood-2013-03-493163 Wise, 2010, Glutamine addiction: a new therapeutic target in cancer, Trends Biochem. Sci., 35, 427, 10.1016/j.tibs.2010.05.003 Wu, 2011, Mitochondrial oxidative stress causes mitochondrial fragmentation via differential modulation of mitochondrial fission-fusion proteins, FEBS J., 278, 941, 10.1111/j.1742-4658.2011.08010.x Yang, 2017, Glutaminolysis: a hallmark of cancer metabolism, Annu. Rev. Biomed. Eng., 19, 163, 10.1146/annurev-bioeng-071516-044546 Yokoi, 2004, Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine, Clin. Cancer Res., 10, 2299, 10.1158/1078-0432.CCR-03-0488 Zalman, 1980, Mitochondrial outer membrane contains a protein producing nonspecific diffusion channels, J. Biol. Chem., 255, 1771, 10.1016/S0021-9258(19)85942-2