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Glutamine at focus: versatile roles in cancer

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  • Published:
Tumor Biology

Abstract

During the past decade, a heightened understanding of metabolic pathways in cancer has significantly increased. It is recognized that many tumor cells are genetically programmed and have involved an abnormal metabolic state. Interestingly, this increased metabolic autonomy generates dependence on various nutrients such as glucose and glutamine. Both of these components participate in various facets of metabolic activity that allow for energy production, synthesis of biomass, antioxidant defense, and the regulation of cell signaling. Here, we outline the emerging data on glutamine metabolism and address the molecular mechanisms underlying glutamine-induced cell survival. We also discuss novel therapeutic strategies to exploit glutamine addiction of certain cancer cell lines.

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Abbreviations

2-HG:

2-Hydroxyglutarate

13CNMR:

Magnetic resonance spectroscopy

α-KG:

α-Ketoglutarate

AMPK:

AMP-activated Ser/Thr protein kinase

AOA:

Aminooxyacetate

BPTES:

Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide

CS:

Citrate synthase

EAA:

Essential amino acids

ER:

Endoplasmic reticulum

ETC:

Electron transfer chain

FADH2 :

II flavin adenine dinucleotide

FH:

Fumarate hydratase

GDH:

Glutamate dehydrogenase

GLS:

Glutaminase

GOT1:

Aspartate transaminase

GPNA:

γ-L-glutamylp-nitroanilide

GS:

Glutamine synthetase (GS)

GSH:

Glutathione

GSSG:

Glutathione disulfide, Hace1, E3 ubiquitin-protein ligase

HIF-1:

Hypoxia-inducible factor-1

HBP:

Hexosamine biosynthetic pathway

IDH:

Isocitrate dehydrogenase

LDH:

Lactate dehydrogenase

L-DON:

6-Diazo-5-oxo-l-norleucine

ME:

Malic enzyme

mTOR:

Mammalian target of rapamycin

NADH:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NEAA:

Nonessential amino acids

NH4+ :

Ammonia

NO:

Nitric oxide

OAA:

Oxalacetate

OXPHOS:

Oxidative phosphorylation

PARP:

Poly(ADP ribose) polymerase

PC:

Pyruvate carboxylase

PDAC:

Pancreatic ductal adenocarcinoma

PEPCK:

Phosphoenol pyruvate carboxylase kinase

PDH:

Pyruvate dehydrogenase

PHD:

Prolyl hydroxylase

PHGDH:

Phosphoglycerate dehydrogenase

PK:

Pyruvate kinase

PSAT1:

Phosphoserine aminotransferase

ROS:

Reactive oxygen species

SCs:

Surviving cells

SCO2:

Cytochrome c oxidase

SDH:

Succinate dehydrogenase

Sirt4:

Mitochondrial ADP-ribosyltransferase

SLC1A5:

Solute linked carrier family 1 member A5

TA:

Aminotransferase

TCA:

Tricarboxylic acid

TDG:

Thymine DNA glycosylase

TNF-α:

Tumor necrosis factor α

References

  1. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.

    Article  CAS  PubMed  Google Scholar 

  2. Warburg O, Posener K. Ueber den Stoffwechsel der Carcinomzelle. Naturwissenschaften. 1924;12:1131–7.

    Article  CAS  Google Scholar 

  3. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.

    Article  CAS  PubMed  Google Scholar 

  4. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. DeBerardinis R, Sayed N, Ditsworth D, Thompson C. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov. 2013;12(11):829–46.

    Article  CAS  PubMed  Google Scholar 

  7. Vander Heiden MG. Exploiting tumor metabolism: challenges for clinical translation. J Clin Invest. 2013;123(9):3648–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21(3):297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, et al. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol. 2014;24(19):2274–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gaglio D, Soldati C, Vanoni M, Alberghina L, Chiaradonna F. Glutamine deprivation induces abortive s-phase rescued by deoxyribonucleotides in k-ras transformed fibroblasts. PLoS One. 2009;4(3), e4715.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458(7239):762–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;481(7381):380–4.

    CAS  Google Scholar 

  13. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496(7443):101–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A. 2008;105(48):18782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 2007;178(1):93–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123(9):3678–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007;104(49):19345–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tardito S, Oudin A, Ahmed SU, Fack F, Keunen O, Zheng L, et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol. 2015;17(12):1556–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, et al. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol. 2014;10:728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zhang J, Fan J, Venneti S, Cross J, Takagi T, Bhinder B, et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell. 2014;56(2):205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eagle H. Nutrition needs of mammalian cells in tissue culture. Science. 1955;122(3168):501–14.

    Article  CAS  PubMed  Google Scholar 

  22. Sauer L, Stayman J, Dauchy R. Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res. 1982;2(10):4090–7.

    Google Scholar 

  23. Bergström J, Fürst P, Norée L, Vinnars E. Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol. 1974;36(6):693–7.

    PubMed  Google Scholar 

  24. Reitzer L, Wice B, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979;254(8):2669–76.

    CAS  PubMed  Google Scholar 

  25. Witte D, Ali N, Carlson N, Younes M. Overexpression of the neutral amino acid transporter ASCT2 in human colorectal adenocarcinoma. Anticancer Res. 2002;22(5):2555–7.

    CAS  PubMed  Google Scholar 

  26. Hassanein M, Hoeksema M, Shiota M, Qian J, Harris B, Chen H, et al. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res. 2013;9(3):560–70.

    Article  CAS  Google Scholar 

  27. Huang F, Zhao Y, Zhao J, Wu S, Jiang Y, Ma H, et al. Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer. Int J Clin Exp Pathol. 2014;7(9):6006–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Q, Hardie R, Hoy A, van Geldermalsen M, Gao D, Fazli L, et al. Targeting ASCT2-Mediated Glutamine Uptake Blocks Prostate Cancer Growth and Tumour Development. J Pathol. 2015. doi:10.1002/path.4518.

  29. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136(3):521–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jeon YJ, Khelifa S, Ratnikov B, Scott DA, Feng Y, Parisi F, et al. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell. 2015;9(27):354–69.

    Article  CAS  Google Scholar 

  31. Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal. 2010;3(119):ra31.

    Article  PubMed  CAS  Google Scholar 

  32. Wellen K, Lu C, Mancuso A, Lemons J, Ryczko M, Dennis J, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010;24(24):2784–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313–24.

    Article  CAS  PubMed  Google Scholar 

  34. Bröer A, Wagner C, Lang F, Bröer S. The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine. Biochem J. 2000;1(349):787–95.

    Article  Google Scholar 

  35. Timmerman L, Holton T, Yuneva M, Louie R, Padró M, Daemen A, et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013;24(4):450–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 2009;69(20):7986–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481(7381):385–8.

    PubMed  PubMed Central  Google Scholar 

  38. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108(49):19611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dang L, White D, Gross S, Bennett B, Bittinger M, Driggers E, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491(7424):364–73.

    Article  CAS  PubMed  Google Scholar 

  41. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shih C, Shilo B, Goldfarb M, Dannenberg A, Weinberg R. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc Natl Acad Sci U S A. 1979;76(11):5714–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Spector D, Varmus H, Bishop J. Nucleotide sequences related to the transforming gene of avian sarcoma virus are present in DNA of uninfected vertebrates. Proc Natl Acad Sci U S A. 1978;75(9):4102–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82.

    Article  CAS  PubMed  Google Scholar 

  45. Medina M, Sánchez-Jiménez F, Márquez J, Rodríguez Quesada A. Núñez de Castro I. Relevance of glutamine metabolism to tumor cell growth. Mol Cell Biochem. 1992;113(1):1–15.

    Article  CAS  PubMed  Google Scholar 

  46. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18(3):207–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cheng T, Sudderth J, Yang C, Mullen A, Jin E, Matés J, et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci U S A. 2011;24(108):8674–9.

    Article  Google Scholar 

  48. Qing G, Li B, Vu A, Skuli N, Walton ZE, Liu X, et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell. 2012;22(5):631–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Terunuma A, Putluri N, Mishra P, Mathé E, Dorsey T, Yi M, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014;124(1):398–412.

    Article  CAS  PubMed  Google Scholar 

  50. Bott AJ, Peng IC, Fan Y, Faubert B, Zhao L, Li J, et al. Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation. Cell Metab. 2015;22(6):1068–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kung HN, Marks JR, Chi JT. Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet. 2011;8, e1002229.

    Article  CAS  Google Scholar 

  52. McCormick F. Ras-related proteins in signal transduction and growth control. Mol Reprod Dev. 1995;42(4):500–6.

    Article  CAS  PubMed  Google Scholar 

  53. Chiaradonna F, Gaglio D, Vanoni M, Alberghina L. Expression of transforming K-Ras oncogene affects mitochondrial function and morphology in mouse fibroblasts. Biochim Biophys Acta. 2006;1757(9-10):1338–56.

    Article  CAS  PubMed  Google Scholar 

  54. Chiaradonna F, Sacco E, Manzoni R, Giorgio M, Vanoni M, Alberghina L. Ras-dependent carbon metabolism and transformation in mouse fibroblasts. Oncogene. 2006;25(39):5391–404.

    Article  CAS  PubMed  Google Scholar 

  55. Vizan P, Boros L, Figueras A, Capella G, Mangues R, Bassilian S, et al. K-ras codon-specific mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] fibroblasts. Cancer Res. 2005;65(13):5512–5.

    Article  CAS  PubMed  Google Scholar 

  56. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Weinberg F, Hamanaka R, Wheaton W, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A. 2010;107(19):8788–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Kong B, Qia C, Erkan M, Kleeff J, Michalski CW. Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels. Front Physiol. 2013;4:246.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514(7524):628–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chakrabarti G, Moore ZR, Luo X, Ilcheva M, Ali A, Padanad M, et al. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab. 2015;3(12). doi:10.1186/s40170-015-0137-1.

  62. Zhang XD, Qin ZH, Wang J. The role of p53 in cell metabolism. Acta Pharmacol Sin. 2010;31(9):1208–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bensaad K, Tsuruta A, Selak M, Vidal M, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126(1):107–20.

    Article  CAS  PubMed  Google Scholar 

  64. Matoba S, Kang J, Patino W, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312(5780):1650–3.

    Article  CAS  PubMed  Google Scholar 

  65. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A. 2010;107(16):7455–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013;493(7434):689–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A. 2010;107(16):7461–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Szeliga M, Obara-Michlewska M, Matyja E, Łazarczyk M, Lobo C, Hilgier W, et al. Transfection with liver-type glutaminase cDNA alters gene expression and reduces survival, migration and proliferation of T98G glioma cells. Glia. 2009;57(9):1014–23.

    Article  PubMed  Google Scholar 

  69. Reid MA, Wang WI, Rosales KR, Welliver MX, Pan M, Kong M. The B55alpha subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol Cell. 2013;50(2):200–11.

    Article  CAS  PubMed  Google Scholar 

  70. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23(5):537–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Haigis M, Guarente L. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20(21):2913–21.

    Article  CAS  PubMed  Google Scholar 

  72. Fernandez-Marcos PJ, Serrano M. Sirt4: the glutamine gatekeeper. Cancer Cell. 2013;23(4):427–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 2013;23(4):450–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013;153(4):840–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cetinbas N, Daugaard M, Mullen AR, Hajee S, Rotblat B, Lopez A, et al. Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction. Oncogene. 2014.

  76. Menon S, Manning B. Common corruption of the mTOR signaling network in human tumors. Oncogene. 2008; Suppl 2:S43–51.

  77. Bentzinger C, Romanino K, Cloëtta D, Lin S, Mascarenhas J, Oliveri F, et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 2008;5:411–24.

    Article  CAS  Google Scholar 

  78. Elstrom R, Bauer D, Buzzai M, Karnauskas R, Harris M, Plas D, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64(11):3892–9.

    Article  CAS  PubMed  Google Scholar 

  79. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey R, Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001;15(11):1406–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ramanathan A, Schreiber S. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A. 2009;106(52):22229–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gingras A, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15(7):807–26.

    Article  CAS  PubMed  Google Scholar 

  82. Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 2012;47(3):349–58.

    Article  CAS  PubMed  Google Scholar 

  83. Shanware NP, Bray K, Eng CH, Wang F, Follettie M, Myers J, et al. Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion. Nat Commun. 2014;5:4900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Onul A, Elseth K, De Vitto H, Paradise W, Vesper B, Tarjan G, et al. Long-term adaptation of the human lung tumor cell line A549 to increasing concentrations of hydrogen peroxide. Tumour Biol. 2012;33(3):739–48.

    Article  CAS  PubMed  Google Scholar 

  85. Vesper B, Onul A, Haines GR, Tarjan G, Xue J, Elseth K, et al. Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines. Tumour Biol. 2013;24(1):203–14.

    Article  CAS  Google Scholar 

  86. Jung C, Ro S, Cao J, Otto N, Kim D. mTOR regulation of autophagy. FEBS Lett. 2010;584(7):1287–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell. 2015;162(2):259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.

    Article  CAS  PubMed  Google Scholar 

  89. Davies S, Sim A, Hardie D. Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. Eur J Biochem. 1990;187(1):183–90.

    Article  CAS  PubMed  Google Scholar 

  90. Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17(1):113–24.

    Article  CAS  PubMed  Google Scholar 

  93. Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L, Kress TR, et al. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature. 2012;483(7391):608–12.

    Article  CAS  PubMed  Google Scholar 

  94. Ma L, Tao Y, Duran A, Llado V, Galvez A, Barger JF, et al. Control of nutrient stress-induced metabolic reprogramming by PKCzeta in tumorigenesis. Cell. 2013;152(3):599–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Muñoz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 2012;3, e248.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Ames B. Dietary Carcinogens and Anticarcinogens. Science. 1983;221(4617):1256–64.

    Article  CAS  PubMed  Google Scholar 

  97. De Vitto H, Mendonça B, Elseth K, Onul A, Xue J, Vesper B, et al. Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism. Tumour Biol. 2013;34(1):403–13.

    Article  PubMed  CAS  Google Scholar 

  98. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J. 1996;313:17–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tu BP, Mohler RE, Liu JC, Dombek KM, Young ET, Synovec RE, et al. Cyclic changes in metabolic state during the life of a yeast cell. Proc Natl Acad Sci U S A. 2007;104(23):16886–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dasgupta S, Soudry E, Mukhopadhyay N, Shao C, Yee J, Lam S, et al. Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. J Cell Physiol. 2012;227(6):2451–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005;11:857–66.

    Article  Google Scholar 

  102. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675–82.

    Article  CAS  PubMed  Google Scholar 

  103. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2015;29(8):887.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 2011;477(7363):225–8.

    Article  CAS  PubMed  Google Scholar 

  105. Rajagopalan KN, Egnatchik RA, Calvaruso MA, Wasti AT, Padanad MS, Boroughs LK, et al. Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells. Cancer Metab. 2015;3:7.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Chowdhury R, Yeoh K, Tian Y, Hillringhaus L, Bagg E, Rose N, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lu C, Ward P, Kapoor G, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ward P, Patel J, Wise D, Abdel-Wahab O, Bennett B, Coller H, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Icard P, Poulain L, Lincet H. Understanding the central role of citrate in the metabolism of cancer cells. Biochim Biophys Acta. 2012;1825(1):111–6.

    CAS  PubMed  Google Scholar 

  110. Hatzivassiliou G, Zhao F, Bauer D, Andreadis C, Shaw A, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8(4):311–21.

    Article  CAS  PubMed  Google Scholar 

  111. Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature. 2012;491(7424):458–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Méndez-Lucas A, Hyroššová P, Novellasdemunt L, Viñals F, Perales JC. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER)stress response gene involved in tumor cell adaptation to nutrient availability. J Biol Chem. 2014;289(32):22090–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Montal ED, Dewi R, Bhalla K, Ou L, Hwang BJ, Ropell AE, et al. PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Mol Cell. 2015;60(4):571–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Klarer AC, O’Neal J, Imbert-Fernandez Y, Clem A, Ellis SR, Clark J, et al. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism. Cancer Metab. 2014;2(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Berg J, Tymoczko J, Stryer L. The glycolytic pathway is tightly controlled. biochemistry. 5th ed. New York, USA: W H Freeman; 2002.

    Google Scholar 

  116. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;9(4):191–8.

    Article  CAS  Google Scholar 

  117. Possemato R, Marks K, Shaul Y, Pacold M, Kim D, Birsoy K, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476(7360):346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kalhan S, Hanson R. Resurgence of serine: an often neglected but indispensable amino acid. J Biol Chem. 2012;287(24):19786–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Locasale J, Grassian A, Melman T, Lyssiotis C, Mattaini K, Bass A, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43(9):869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Maddocks O, Berkers C, Mason S, Zheng L, Blyth K, Gottlieb E, et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2013;493(7433):542–6.

    Article  CAS  PubMed  Google Scholar 

  121. Amelio I, Markert E, Rufini A, Antonov A, Sayan B, Tucci P, et al. p73 regulates serine biosynthesis in cancer. Oncogene. 2014;33(42):5039–46.

    Article  CAS  PubMed  Google Scholar 

  122. Duthie S. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis. 2011;34(1):101–9.

    Article  CAS  PubMed  Google Scholar 

  123. Piskac-Collier A, Monroy C, Lopez M, Cortes A, Etzel C, Greisinger A, et al. Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. Genes Chromosomes Cancer. 2011;50(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  124. Farber S, Diamond L, Mercer R, Sylvester R, Wolff J. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948;238:787–93.

    Article  CAS  PubMed  Google Scholar 

  125. Acharya A, Das I, Chandhok D, Saha T. Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev. 2010;3(1):23–34.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Holmström K, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014;15(6):411–21.

    Article  PubMed  CAS  Google Scholar 

  127. Cooke M, Evans M, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003;17(10):1195–214.

    Article  CAS  PubMed  Google Scholar 

  128. Marnett L. Oxyradicals and DNA damage. Carcinogenesis. 2000;21(3):361–70.

    Article  CAS  PubMed  Google Scholar 

  129. Valko M, Rhodes C, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1–40.

    Article  CAS  PubMed  Google Scholar 

  130. Amores-Sánchez M, Medina M. Glutamine, as a precursor of glutathione, and oxidative stress. Mol Genet Metab. 1999;67(2):100–5.

    Article  PubMed  Google Scholar 

  131. Roth E, Oehler R, Manhart N, Exner R, Wessner B, Strasser E, et al. Regulative potential of glutamine—relation to glutathione metabolism. Nutrition. 2002;18(3):217–21.

    Article  CAS  PubMed  Google Scholar 

  132. Estrela J, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci. 2006;43(2):143–81.

    Article  CAS  PubMed  Google Scholar 

  133. Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez M, García-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med. 2013;65:750–64.

    Article  PubMed  CAS  Google Scholar 

  134. Hayes J, McMahon M. The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer. Mol Cell. 2006;21(6):732–4.

    Article  CAS  PubMed  Google Scholar 

  135. Kensler T, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis. 2010;31(1):90–9.

    Article  CAS  PubMed  Google Scholar 

  136. Kaspar J, Niture S, Jaiswal A. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22(1):66–79.

    Article  CAS  PubMed  Google Scholar 

  138. Afonyushkin T, Oskolkova OV, Philippova M, Resink TJ, Erne P, Binder BR, et al. Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependentmechanism: novel point of convergence between electrophilic and unfolded protein stress pathways. Arterioscler Thromb Vasc Biol. 2010;30(5):1007–13.

    Article  CAS  PubMed  Google Scholar 

  139. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, et al. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem. 2001;276(24):20858–65.

    Article  CAS  PubMed  Google Scholar 

  140. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015;47(12):1475–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47.

    Article  CAS  PubMed  Google Scholar 

  142. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12(10):685–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. DeBerardinis R, Lum J, Hatzivassiliou G, Thompson C. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;1:11–20.

    Article  CAS  Google Scholar 

  145. Meng M, Chen S, Lao T, Liang D, Sang N. Nitrogen anabolism underlies the importance of glutaminolysis in proliferating cells. Cell Cycle. 2014;9(19):3921–32.

    Article  CAS  Google Scholar 

  146. Eng C, Abraham R. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy. 2010;7:968–70.

    Article  Google Scholar 

  147. Mariño G, Kroemer G. Ammonia: a diffusible factor released by proliferating cells that induces autophagy. Sci Signal. 2010;124:pe19.

    Google Scholar 

  148. Cheong H, Lindsten T, Thompson C. Autophagy and ammonia. Autophagy. 2012;1:122–3.

    Article  CAS  Google Scholar 

  149. Green D, Galluzzi L, Kroemer G. Cell biology. Metabolic control of cell death. Science. 2014;345(6203):1250256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Weinberg S, Chandel N. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015;1:9–15.

    Google Scholar 

  151. Ahluwalia G, Grem J, Hao Z, Cooney D. Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther. 1990;46(2):243–71.

    Article  CAS  PubMed  Google Scholar 

  152. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15(1):110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Seltzer M, Bennett B, Joshi A, Gao P, Thomas A, Ferraris D, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70(22):8981–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Thornburg J, Nelson K, Clem B, Lane A, Arumugam S, Simmons A, et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 2008;10(5):R84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Stalnecker C, Ulrich SL Y, Ramachandran S, McBrayer M, DeBerardinis R, Cerione R, et al. Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells. Proc Natl Acad Sci U S A. 2015;112(2):394–9.

    Article  CAS  PubMed  Google Scholar 

  156. Narta U, Kanwar S, Azmi W. Pharmacological and clinical evaluation of L-asparaginase in the treatment of leukemia. Crit Rev Oncol Hematol. 2007;61(3):208–21.

    Article  PubMed  Google Scholar 

  157. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene. 2015. doi:10.1038/onc.2015.447.

  159. Li B, Simon MC. Molecular pathways: targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res. 2013;1:19(21). doi:10.1158/1078-0432.

    Google Scholar 

  160. Kim JW, Amin AR, Shin DM. Chemoprevention of head and neck cancer with green tea polyphenols. Cancer Prev Res (Phila). 2010;3(8):900–9.

    Article  CAS  Google Scholar 

  161. Qu W, Oya S, Lieberman BP, Ploessl K, Wang L, Wise DR, et al. Preparation and characterization of L-[5-11C]-glutamine for metabolic imaging of tumors. J Nucl Med. 2012;53(1):98–105.

    Article  CAS  PubMed  Google Scholar 

  162. Lieberman BP, Ploessl K, Wang L, Qu W, Zha Z, Wise DR, et al. PET imaging of glutaminolysis in tumors by 18F-(2S,4R)4-fluoroglutamine. J Nucl Med. 2011;52(12):1947–55.

    Article  CAS  PubMed  Google Scholar 

  163. Venneti S, Dunphy M, Zhang H, Pitter K, Zanzonico P, Campos C, et al. Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Transl Med. 2015;7(274):274ra17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Metallo CM, Vander Heiden MG. Understanding metabolic regulation and its influence on cell physiology. Mol Cell. 2013;49(3):388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Metallo C, Walther J, Stephanopoulos G. Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J Biotechnol. 2009;144(3):167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Yuneva MO, Fan TW, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012;15(2):157–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mayers J, Vander HM. Famine versus feast: understanding the metabolism of tumors in vivo. Trends Biochem Sci. 2015.

  168. Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 2015;75(3):544–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was funded by the Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Brazil (grant number BEX 9281/13-4).

Author contributions

Study concept and design: Humberto De Vitto; drafting of the manuscript: Humberto De Vitto, Juan Pérez-Valencia, James A. Radosevich; critical revision of the manuscript for intellectual content: Humberto De Vitto, Juan Pérez-Valencia, James A. Radosevich.

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  1. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy

    Humberto De Vitto

  2. University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Juan Pérez-Valencia

  3. University of Illinois at Chicago, Chicago, IL, USA

    James A. Radosevich

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  1. Humberto De Vitto
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  3. James A. Radosevich
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De Vitto, H., Pérez-Valencia, J. & Radosevich, J.A. Glutamine at focus: versatile roles in cancer. Tumor Biol. 37, 1541–1558 (2016). https://doi.org/10.1007/s13277-015-4671-9

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