Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime?

Relative to other neutral amino acid transporters, the expression levels of ASCT2 and LAT1, are coordinately elevated in a wide spectrum of primary human cancers, suggesting that they are frequently co-opted to support the "tumor metabolome". Each has recently been shown to play important roles in the growth and survival of cancer cell lines, making them potential targets for cancer therapy. The properties and putative relationship of these two amino acid exchangers are discussed in the context of their demonstrated utility in cancer biology, including cellular growth and survival signaling and integrated links to the mammalian target-of-rapamycin (mTOR) kinase.

[1]  D. Haüssinger.  Nitrogen metabolism in liver: structural and functional organization and physiological relevance. , 1990, The Biochemical journal.

[2]  Hong Wang,et al.  Platelet‐derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: Role in cell growth , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  W. Souba,et al.  Protein kinase C regulates nutrient uptake and growth in hepatoma cells. , 1998, Surgery.

[4]  H. Eagle,et al.  Amino acid metabolism in mammalian cell cultures. , 1959, Science.

[5]  W. Souba,et al.  Glutamine transport in isolated human hepatocytes and transformed liver cells , 1995, Hepatology.

[6]  M. Palacín,et al.  CATs and HATs: the SLC7 family of amino acid transporters , 2004, Pflügers Archiv.

[7]  J. Mcgivan,et al.  The bovine renal epithelial cell line NBL-1 expresses a broad specificity Na(+)-dependent neutral amino acid transport system (System Bo) similar to that in bovine renal brush border membrane vesicles. , 1992, Biochimica et biophysica acta.

[8]  J. Blenis,et al.  Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression , 2004, Oncogene.

[9]  W. Souba,et al.  Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines. , 1996, Annals of surgery.

[10]  B. Stevens.  Amino Acid Transport in Intestine , 1992 .

[11]  M. Kilberg,et al.  Characteristics of an amino acid transport system in rat liver for glutamine, asparagine, histidine, and closely related analogs. , 1980, The Journal of biological chemistry.

[12]  Y. Kanai,et al.  Expression and functional characterization of the system L amino acid transporter in KB human oral epidermoid carcinoma cells. , 2004, Cancer letters.

[13]  Y. Kanai,et al.  Cloning and Functional Characterization of a System ASC-like Na+-dependent Neutral Amino Acid Transporter* , 1996, The Journal of Biological Chemistry.

[14]  W. Gahl,et al.  Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder , 2004, Nature Genetics.

[15]  V. Ganapathy,et al.  Molecular and functional characterization of intestinal Na(+)-dependent neutral amino acid transporter B0. , 1997, The American journal of physiology.

[16]  T. V. Kolesnikova,et al.  The Light Chain of CD98 Is Identified as E16/TA1 Protein* , 1998, The Journal of Biological Chemistry.

[17]  S. Bröer,et al.  Neutral amino acid transporter ASCT2 displays substrate-induced Na+ exchange and a substrate-gated anion conductance. , 2000, The Biochemical journal.

[18]  Y. Kanai,et al.  Expression of L‐type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models , 2001, Journal of surgical oncology.

[19]  P. Scardino,et al.  Expression of neutral amino acid transporter ASCT2 in human prostate. , 2003, Anticancer research.

[20]  B. Mackenzie,et al.  Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family , 2004, Pflügers Archiv.

[21]  S. Bröer,et al.  Expression of the surface antigen 4F2hc affects system-L-like neutral-amino-acid-transport activity in mammalian cells. , 1997, The Biochemical journal.

[22]  E. Wright,et al.  Multiple transport pathways for neutral amino acids in rabbit jejunal brush border vesicles , 1982, The Journal of Membrane Biology.

[23]  M. Palacín,et al.  Molecular biology of mammalian plasma membrane amino acid transporters. , 1998, Physiological reviews.

[24]  I. Gow,et al.  L-leucine transport in human breast cancer cells (MCF-7 and MDA-MB-231): kinetics, regulation by estrogen and molecular identity of the transporter. , 2004, Biochimica et biophysica acta.

[25]  D. Witte,et al.  Overexpression of the neutral amino acid transporter ASCT2 in human colorectal adenocarcinoma. , 2002, Anticancer research.

[26]  K. Behar,et al.  In vivo nuclear magnetic resonance studies of glutamate-gamma-aminobutyric acid-glutamine cycling in rodent and human cortex: the central role of glutamine. , 2001, The Journal of nutrition.

[27]  M. Medina,et al.  Interchange of amino acids between tumor and host. , 1992, Biochemical medicine and metabolic biology.

[28]  W. Souba,et al.  Determinants of glutamine dependence and utilization by normal and tumor‐derived breast cell lines , 1998, Journal of cellular physiology.

[29]  E. Babu,et al.  Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. , 2002, Biochimica et biophysica acta.

[30]  H. Stuhlmann,et al.  CD98hc (SLC3A2) mediates integrin signaling. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Bröer,et al.  Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19 , 2004, Nature Genetics.

[32]  H. Christensen,et al.  Role of amino acid transport and countertransport in nutrition and metabolism. , 1990, Physiological reviews.

[33]  Andreas Rolfs,et al.  The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins , 2004, Pflügers Archiv.

[34]  K. Osen,et al.  Cell‐specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle , 2002, The European journal of neuroscience.

[35]  M. Ito,et al.  Molecular events involved in up-regulating human Na+-independent neutral amino acid transporter LAT1 during T-cell activation. , 2001, The Biochemical journal.

[36]  T. Pawlik,et al.  Phorbol esters rapidly attenuate glutamine uptake and growth in human colon carcinoma cells. , 2000, The Journal of surgical research.

[37]  J. Rasko,et al.  Hartnup disorder: Polymorphisms identified in the neutral amino acid transporter SLC1A5 , 2002, Journal of Inherited Metabolic Disease.

[38]  W. Souba,et al.  Glutamine transport and human hepatocellular transformation. , 1999, JPEN. Journal of parenteral and enteral nutrition.

[39]  J. McNamara,et al.  Cloning and expression of a novel Na(+)-dependent neutral amino acid transporter structurally related to mammalian Na+/glutamate cotransporters. , 1993, The Journal of biological chemistry.

[40]  D. Oxender,et al.  DISTINCT MEDIATING SYSTEMS FOR THE TRANSPORT OF NEUTRAL AMINO ACIDS BY THE EHRLICH CELL. , 1963, The Journal of biological chemistry.

[41]  Y. Kanai,et al.  Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. , 2002, Molecular pharmacology.

[42]  V. Ganapathy,et al.  Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. , 1999, Biochemical and biophysical research communications.

[43]  M. Kavanaugh,et al.  ASCT-1 Is a Neutral Amino Acid Exchanger with Chloride Channel Activity* , 1996, The Journal of Biological Chemistry.

[44]  William C Reinhold,et al.  Membrane Transporters and Channels , 2004, Cancer Research.

[45]  S. Bröer,et al.  Function and structure of heterodimeric amino acid transporters. , 2001, American journal of physiology. Cell physiology.

[46]  S. Bröer.  Adaptation of plasma membrane amino acid transport mechanisms to physiological demands , 2002, Pflügers Archiv.

[47]  V. Ganapathy,et al.  Sodium-dependent homo- and hetero-exchange of neutral amino acids mediated by the amino acid transporter ATB degree. , 1998, Biochemical and biophysical research communications.

[48]  D. A. Wolf,et al.  Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to Schistosoma mansoni amino acid permease and Caenorhabditis elegans gene products. , 1996, Cancer research.

[49]  C. Tailor,et al.  A Sodium-Dependent Neutral-Amino-Acid Transporter Mediates Infections of Feline and Baboon Endogenous Retroviruses and Simian Type D Retroviruses , 1999, Journal of Virology.

[50]  H. G. Windmueller,et al.  Uptake and metabolism of plasma glutamine by the small intestine. , 1974, The Journal of biological chemistry.

[51]  Hong-Sheng Wang,et al.  Characterization of L-glutamine transport by a human neuroblastoma cell line. , 2002, American journal of physiology. Cell physiology.

[52]  M. Hediger,et al.  The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. , 2003, European journal of pharmacology.

[53]  L. Baggetto,et al.  Deviant energetic metabolism of glycolytic cancer cells. , 1992, Biochimie.

[54]  V. Ganapathy,et al.  Tyrosine phosphorylation-and epidermal growth factor-dependent regulation of the sodium-coupled amino acid transporter B0 in the human placental choriocarcinoma cell line JAR. , 1997, Biochimica et biophysica acta.

[55]  G. Mann,et al.  Amino acid transport by small intestinal, hepatic, and pancreatic epithelia. , 1995, Gastroenterology.

[56]  S. Thorgeirsson,et al.  Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer , 2002, Hepatology.

[57]  Eiji Takeda,et al.  Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98)* , 1998, The Journal of Biological Chemistry.

[58]  H. Christensen,et al.  A distinct Na+-requiring transport system for alanine, serine, cysteine, and similar amino acids. , 1967, The Journal of biological chemistry.

[59]  Y. Kanai,et al.  Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in oral squamous cell carcinoma and its precusor lesions. , 2004, Anticancer research.

[60]  W. Souba,et al.  Adaptive regulation of amino acid transport in nutrient-deprived human hepatomas. , 1996, American journal of surgery.

[61]  C. Proud,et al.  Regulation of mammalian translation factors by nutrients. , 2002, European journal of biochemistry.

[62]  T. Masuko,et al.  Inhibition of tumor cell growth in vitro by murine monoclonal antibodies that recognize a proliferation-associated cell surface antigen system in rats and humans. , 1986, Cancer research.

[63]  F. Verrey.  System L: heteromeric exchangers of large, neutral amino acids involved in directional transport , 2003, Pflügers Archiv.

[64]  H. Gaugitsch,et al.  A novel transiently expressed, integral membrane protein linked to cell activation. Molecular cloning via the rapid degradation signal AUUUA. , 1992, The Journal of biological chemistry.

[65]  H. Endou,et al.  Expression of L-type amino acid transporter 1 in a rat model of liver metastasis: positive correlation with tumor size. , 2001, Cancer detection and prevention.

[66]  C. Thompson,et al.  Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. , 2002, Molecular biology of the cell.

[67]  M. Hediger,et al.  The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects , 2004, Pflügers Archiv.

[68]  C. Boyd,et al.  RNA interference‐induced reduction in CD98 expression suppresses cell fusion during syncytialization of human placental BeWo cells , 2004, FEBS letters.

[69]  J. Rasko,et al.  The RD114/simian type D retrovirus receptor is a neutral amino acid transporter. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[70]  C. Meier,et al.  Activation of system L heterodimeric amino acid exchangers by intracellular substrates , 2002, The EMBO journal.

[71]  H. Eagle,et al.  Nutrition needs of mammalian cells in tissue culture. , 1955, Science.

[72]  D. Lavillette,et al.  The Envelope Glycoprotein of Human Endogenous Retrovirus Type W Uses a Divergent Family of Amino Acid Transporters/Cell Surface Receptors , 2002, Journal of Virology.

[73]  M. Mita,et al.  The Molecular Target of Rapamycin (mTOR) as a Therapeutic Target Against Cancer , 2003, Cancer biology & therapy.

[74]  A. Meijer.  Amino acids as regulators and components of nonproteinogenic pathways. , 2003, The Journal of nutrition.

[75]  J. Best,et al.  Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer , 2005, Journal of cellular physiology.

[76]  M. Palacín,et al.  Identification of LAT4, a Novel Amino Acid Transporter with System L Activity* , 2005, Journal of Biological Chemistry.

[77]  D. Häussinger,et al.  Mammalian Amino Acid Transport , 1992, Springer US.

[78]  Y. Kanai,et al.  Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. , 2001, Biochimica et biophysica acta.

[79]  E. Eigenbrodt,et al.  The tumor metabolome. , 2003, Anticancer research.

[80]  W. Souba,et al.  Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[81]  S. Cerdán,et al.  Cerebral glucose metabolism and the glutamine cycle as detected by in vivo and in vitro 13 C NMR spectroscopy , 2004, Neurochemistry International.

[82]  H. Christensen,et al.  Na+-dependent transport of basic, zwitterionic, and bicyclic amino acids by a broad-scope system in mouse blastocysts. , 1985, The Journal of biological chemistry.

[83]  I. Paulsen,et al.  New Glycoprotein-Associated Amino Acid Transporters , 1999, The Journal of Membrane Biology.

[84]  T. Vary,et al.  Epidermal growth factor activation of intestinal glutamine transport is mediated by mitogen-activated protein kinases , 2003, Journal of Gastrointestinal Surgery.

[85]  B. Fuchs,et al.  Inducible antisense RNA targeting amino acid transporter ATB0/ASCT2 elicits apoptosis in human hepatoma cells. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[86]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[87]  H. Mitsuya,et al.  Down-Regulation of CD98 in Melphalan-Resistant Myeloma Cells with Reduced Drug Uptake , 2000, Acta Haematologica.

[88]  Jan Albrecht,et al.  Increased expression of a glutamine transporter SNAT3 is a marker of malignant gliomas , 2004, Neuroreport.

[89]  S. Bröer,et al.  Molecular Cloning of Mouse Amino Acid Transport System B0, a Neutral Amino Acid Transporter Related to Hartnup Disorder* , 2004, Journal of Biological Chemistry.

[90]  D. Lavillette,et al.  N-Linked Glycosylation and Sequence Changes in a Critical Negative Control Region of the ASCT1 and ASCT2 Neutral Amino Acid Transporters Determine Their Retroviral Receptor Functions , 2003, Journal of Virology.

[91]  V. Ganapathy,et al.  Cloning of the Sodium-dependent, Broad-scope, Neutral Amino Acid Transporter Bo from a Human Placental Choriocarcinoma Cell Line* , 1996, The Journal of Biological Chemistry.

[92]  Y. Kanai,et al.  Heterodimeric amino acid transporters: molecular biology and pathological and pharmacological relevance. , 2001, Current drug metabolism.

[93]  I. Goto,et al.  Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma. , 1992, Cancer research.

[94]  R. North,et al.  Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. , 1993, The Journal of biological chemistry.

[95]  C. Swanson,et al.  Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. , 1993, British Journal of Cancer.

[96]  N. Thompson,et al.  TA1, a highly conserved oncofetal complementary DNA from rat hepatoma, encodes an integral membrane protein associated with liver development, carcinogenesis, and cell activation. , 1995, Cancer research.

[97]  C. Proud,et al.  Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. , 2003, The Biochemical journal.

[98]  C. Hirayama,et al.  Plasma amino acid patterns in hepatocellular carcinoma. , 1987, Biochemical medicine and metabolic biology.

[99]  G. Siegal,et al.  Amino acid transport systems modulate human tumor cell growth and invasion: a working hypothesis. , 1995, Medical hypotheses.

[100]  B. Bode.  Recent molecular advances in mammalian glutamine transport. , 2001, The Journal of nutrition.

[101]  H. Eagle,et al.  The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. , 1956, The Journal of biological chemistry.

[102]  C. Sawyers.  Will mTOR inhibitors make it as cancer drugs? , 2003, Cancer cell.

[103]  E. Babu,et al.  Identification of a Novel System L Amino Acid Transporter Structurally Distinct from Heterodimeric Amino Acid Transporters* , 2003, Journal of Biological Chemistry.

[104]  J. Mccoy,et al.  Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis , 2000, Nature.

[105]  C. Thompson,et al.  Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. , 2003, Cancer research.

[106]  L. Kühn,et al.  Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity , 2000, Pflügers Archiv.

[107]  Miguel Angel Medina,et al.  Relevance of glutamine metabolism to tumor cell growth , 1992, Molecular and Cellular Biochemistry.

[108]  M. Lane,et al.  Expression of a novel insulin-activated amino acid transporter gene during differentiation of 3T3-L1 preadipocytes into adipocytes. , 1995, Biochemical and biophysical research communications.

[109]  M. Honda,et al.  α‐fetoprotein‐producing hepatoma cell lines share common expression profiles of genes in various categories demonstrated by cDNA microarray analysis , 2001 .

[110]  T. Golub,et al.  The Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation , 2002, Molecular and Cellular Biology.

[111]  M. Younes,et al.  Expression of the neutral amino acids transporter ASCT1 in esophageal carcinomas. , 2000, Anticancer research.

[112]  M. Reith,et al.  Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6 , 2004, Pflügers Archiv.

[113]  M. Rennie,et al.  Bidirectional substrate fluxes through the System N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver , 2004, The Journal of physiology.

[114]  A. Bröer,et al.  The Astroglial ASCT2 Amino Acid Transporter as a Mediator of Glutamine Efflux , 1999, Journal of neurochemistry.

[115]  J. Albrecht,et al.  Glutamine transport in C6 glioma cells shows ASCT2 system characteristics , 2003, Neurochemistry International.

[116]  J. Crespo,et al.  The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine , 2002, Proceedings of the National Academy of Sciences of the United States of America.