Oncometabolic mutation IDH1 R132H confers a metforminhypersensitive phenotype

Oncotarget

Volumn 6, Issue 14, 2015, Pages 12279-12296

  Cuyàs, Elisabet ^a,b   Fernández Arroyo, Salvador ^c   Corominas Faja, Bruna ^a,b   Rodríguez Gallego, Esther ^c   Bosch Barrera, Joaquim ^a,b   Martin Castillo, Begoña ^a,b   De Llorens, Rafael ^d   Joven, Jorge ^c   Menendez, Javier A ^a,b  

^a CATALAN INSTITUTE OF ONCOLOGY   (Spain)

^b GIRONA BIOMEDICAL RESEARCH INSTITUTE IDIBGI   (Spain)

^c INSTITUT D INVESTIGACIÓ SANITÀRIA PERE VIRGILI IISPV   (Spain)

^d UNIVERSITY OF GIRONA   (Spain)

Author keywords

Anaplerosis; Cancer; IDH1; Metformin; Oncometabolites

Indexed keywords

2 HYDROXYGLUTARIC ACID; 2 OXOGLUTARIC ACID; AGI 5198; ARGININE; CARBON; ENZYME INHIBITOR; GLUTAMINE; HISTIDINE; ISOCITRATE DEHYDROGENASE 1; METFORMIN; PHENFORMIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; TRICARBOXYLIC ACID; UNCLASSIFIED DRUG; ISOCITRATE DEHYDROGENASE; MUTANT PROTEIN;

AMINO ACID SUBSTITUTION; ARTICLE; BREAST EPITHELIUM CELL; CANCER CELL; CARBON SOURCE; CELL METABOLISM; CELL PROLIFERATION; CHEMOSENSITIVITY; CITRIC ACID CYCLE; CLONOGENESIS; CONTROLLED STUDY; DRUG POTENTIATION; DRUG TARGETING; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME SYNTHESIS; GENE MUTATION; GENETIC ENGINEERING; HUMAN; HUMAN CELL; IDH1 GENE; METABOLOMICS; MICROARRAY ANALYSIS; MITOCHONDRIAL ENERGY TRANSFER; MITOCHONDRION; PHENOTYPE; BRAIN TUMOR; GENETICS; METABOLISM; MUTATION; TUMOR CELL LINE;

BRAIN NEOPLASMS; CELL LINE, TUMOR; HUMANS; ISOCITRATE DEHYDROGENASE; METFORMIN; MUTANT PROTEINS; MUTATION; PHENOTYPE;

EID: 84931362449     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.3733     Document Type: Article

References (89)

1. Frezza C, Pollard PJ, Gottlieb E. Inborn and acquired metabolic defects in cancer. J Mol Med (Berl). 2011; 89:213-20.
2. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012; 18:5562-71.
3. Yang M, Soga T, Pollard PJ, Adam J. The emerging role of fumarate as an oncometabolite. Front Oncol. 2012; 2:85.
4. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013; 123:3652-8.
5. Krell D, Mulholland P, Frampton AE, Krell J, Stebbing J, Bardella C. IDH mutations in tumorigenesis and their potential role as novel therapeutic targets. Future Oncol. 2013; 9:1923-35.
6. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013; 3:730-41.
7. Adam J, Yang M, Soga T, Pollard PJ. Rare insights into cancer biology. Oncogene. 2014; 33:2547-56.
8. Morin A, Letouzé E, Gimenez-Roqueplo AP, Favier J. Oncometabolites-driven tumorigenesis: From genetics to targeted therapy. Int J Cancer. 2014; 135:2237-48.
9. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2014 Nov 11. doi: 10.1038/nrendo.2014.188. [Epub ahead of print].
10. Piruat JI, Millán-Uclés A. Genetically modeled mice with mutations in mitochondrial metabolic enzymes for the study of cancer. Front Oncol. 2014 Jul 30; 4:200.
11. Menendez JA, Alarcón T, Joven J. Gerometabolites: the pseudohypoxic aging side of cancer oncometabolites. Cell Cycle. 2014; 13:699-709.
12. Menendez JA, Alarcón T. Metabostemness: a new cancer hallmark. Front Oncol. 2014; 4:262.
13. Menendez JA, Corominas-Faja B, Cuyàs E, Alarcón T. Metabostemness: Metaboloepigenetic reprogramming of cancer stem-cell functions. Oncoscience. 2015; 1:803-6.
14. Nordgren KK, Skildum AJ. The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer. Eur J Clin Invest. 2015; 45 Suppl 1:9-15.
15. Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005; 14:2231-9.
16. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006; 25:4675-82.
17. Cervera AM, Bayley JP, Devilee P, McCreath KJ. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer. 2009; 8:89.
18. Bardella C, El-Bahrawy M, Frizzell N, Adam J, Ternette N, Hatipoglu E, Howarth K, O'Flaherty L, Roberts I, Turner G, Taylor J, Giaslakiotis K, Macaulay VM, Harris AL, Chandra A, Lehtonen HJ, Launonen V, Aaltonen LA, Pugh CW, Mihai R, Trudgian D, Kessler B, Baynes JW, Ratcliffe PJ, Tomlinson IP, Pollard PJ. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol. 2011; 225:4-11.
19. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL. 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. 2012; 26:1326-38.
20. Sullivan LB, Martinez-Garcia E, Nguyen H, Mullen AR, Dufour E, Sudarshan S, Licht JD, Deberardinis RJ, Chandel NS. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol Cell. 2013; 51:236-48.
21. Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI Jr, Jahromi MS, Xekouki P, Szarek E, Walker RL, Lasota J, Raffeld M, Klotzle B, Wang Z, Jones L, Zhu Y, Wang Y, Waterfall JJ, O'Sullivan MJ, Bibikova M, Pacak K, Stratakis C, Janeway KA, Schiffman JD, Fan JB, Helman L, Meltzer PS. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013; 3:648-57.
22. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-?B signaling. J Biol Chem. 2014; 289:24691-9.
23. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765-73.
24. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224:334-43.
25. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, Schenkein DP, Hezel AF, Ancukiewicz M, Liebman HM, Kwak EL, Clark JW, Ryan DP, Deshpande V, Dias-Santagata D, Ellisen LW, Zhu AX, Iafrate AJ. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broadbased tumor genotyping. Oncologist. 2012;17:72-9.
26. Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR, Andersen JB, Jiang W, Savich GL, Tan TX, Auman JT, Hoskins JM, Misher AD, Moser CD, Yourstone SM, Kim JW, Cibulskis K, Getz G, Hunt HV, Thorgeirsson SS, Roberts LR, Ye D, Guan KL, Xiong Y, Qin LX, Chiang DY. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32:3091-100.
27. Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, Gurumurthy S, Akbay EA, Sia D, Cornella H, Miltiadous O, Walesky C, Deshpande V, Zhu AX, Hezel AF, Yen KE, Straley KS, Travins J, Popovici-Muller J, Gliser C, Ferrone CR, Apte U, Llovet JM, Wong KK, Ramaswamy S, Bardeesy N. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Nature. 2014; 513:110-4.
28. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739-44.
29. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17:225-34.
30. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19:17-30.
31. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, Kawamura A. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011; 12:463-9.
32. Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, Weinstock DM, Sharp KA, Thompson CB. Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene. 2012; 31:2491-8.
33. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zúñiga-Pflücker JC, Mak TW. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012; 488:656-9.
34. Jin G, Reitman ZJ, Duncan CG, Spasojevic I, Gooden DM, Rasheed BA, Yang R, Lopez GY, He Y, McLendon RE, Bigner DD, Yan H. Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer Res. 2013; 73:496-501.
35. Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, Stevenson HS, Karoly ED, Chan K, Samanta S, Prieto D, Hsu TY, Kurley SJ, Putluri V, Sonavane R, Edelman DC, Wulff J, Starks AM, Yang Y, Kittles RA, Yfantis HG, Lee DH, Ioffe OB, Schiff R, Stephens RM, Meltzer PS, Veenstra TD, Westbrook TF, Sreekumar A, Ambs S. MYCdriven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014; 124:398-412.
36. Tang X, Lin CC, Spasojevic I, Iversen ES, Chi JT, Marks JR. A joint analysis of metabolomics and genetics of breast cancer. Breast Cancer Res. 2014; 16:415.
37. Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, Rabinowitz JD. Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite d-2-Hydroxyglutarate. ACS Chem Biol. 2014 Nov 18. [Epub ahead of print].
38. Davis M, Pragani R, Popovici-Muller J, Gross S, Thorne N, Salituro F, Fantin V, Straley K, Su M, Dang L, Simeonov A, Shen M, Boxer MB. ML309: A potent inhibitor of R132H mutant IDH1 capable of reducing 2-hydroxyglutarate production in U87 MG glioblastoma cells. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.2012 Apr 16 [updated 2013 May 8].
39. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013; 340:622-6.
40. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013; 340:626-30.
41. Garrett-Bakelman FE, Melnick AM. Differentiation therapy for IDH1/2 mutant malignancies. Cell Res. 2013; 23:975-7.
42. Davis MI, Gross S, Shen M, Straley KS, Pragani R, Lea WA, Popovici-Muller J, DeLaBarre B, Artin E, Thorne N, Auld DS, Li Z, Dang L, Boxer MB, Simeonov A. Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1. J Biol Chem. 2014; 289:13717-25.
43. Elhammali A, Ippolito JE, Collins L, Crowley J, Marasa J, Piwnica-Worms D. A high-throughput fluorimetric assay for 2-hydroxyglutarate identifies Zaprinast as a glutaminase inhibitor. Cancer Discov. 2014; 4:828-39.
44. Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, He T, Shi C, Bedel O, McLean LR, Le-Strat F, Zhang Y, Marquette JP, Gao Q, Zhang B, Rak A, Hoffmann D, Rooney E, Vassort A, Englaro W, Li Y, Patel V, Adrian F, Gross S, Wiederschain D, Cheng H, Licht S. Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule. J Biol Chem. 2015;290:762-74.
45. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70:8981-7.
46. Navis AC, Niclou SP, Fack F, Stieber D, van Lith S, Verrijp K, Wright A, Stauber J, Tops B, Otte-Holler I, Wevers RA, van Rooij A, Pusch S, von Deimling A, Tigchelaar W, van Noorden CJ, Wesseling P, Leenders WP. Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and a-KG. Acta Neuropathol Commun. 2013; 1:18.
47. Borodovsky A, Salmasi V, Turcan S, Fabius AW, Baia GS, Eberhart CG, Weingart JD, Gallia GL, Baylin SB, Chan TA, Riggins GJ. 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget. 2013; 4:1737-47.
48. Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, Viale A, Riggins GJ, Chan TA. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine. Oncotarget. 2013;4:1729-36.
49. DeLaBarre B, Hurov J, Cianchetta G, Murray S, Dang L. Action at a distance: allostery and the development of drugs to target cancer cell metabolism. Chem Biol. 2014; 21:1143-61.
50. Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, Slocum KL, Pu M, Lin F, Vickers C, Joud-Caldwell C, Chung F, Yin H, Handly ED, Straub C, Growney JD, Vander Heiden MG, Murphy AN, Pagliarini R, Metallo CM. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 2014;74:3317-31.
51. Grassian AR, Lin F, Barrett R, Liu Y, Jiang W, Korpal M, Astley H, Gitterman D, Henley T, Howes R, Levell J, Korn JM, Pagliarini R. Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT). J Biol Chem. 2012; 287:42180-94.
52. Bochner BR, Gadzinski P, Panomitros E. Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res. 2001; 11:1246-1255.
53. Bochner BR. Global phenotypic characterization of bacteria. FEMS Microbiol Rev. 2009; 33:191-205.
54. Bochner BR, Siri M, Huang RH, Noble S, Lei XH, Clemons PA, Wagner BK. Assay of the multiple energy-producing pathways of mammalian cells. PLoS One. 2011; 6:e18147.
55. Shea A, Wolcott M, Daefler S, Rozak DA. Biolog phenotype microarrays. Methods Mol Biol. 2012; 881:331-373.
56. Mackie AM, Hassan KA, Paulsen IT, Tetu SG. Biolog Phenotype Microarrays for phenotypic characterization of microbial cells. Methods Mol Biol. 2014; 1096:123-130.
57. Cuyàs E, Corominas-Faja B, Menendez JA. The nutritional phenome of EMT-induced cancer stem-like cells. Oncotarget. 2014; 5:3970-82.
58. Fendt SM, Bell EL, Keibler MA, Davidson SM, Wirth GJ, Fiske B, Mayers JR, Schwab M, Bellinger G, Csibi A, Patnaik A, Blouin MJ, Cantley LC, Guarente L, Blenis J, Pollak MN, Olumi AF, Vander Heiden MG, Stephanopoulos G. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 2013; 73:4429-38.
59. Javeshghani S, Zakikhani M, Austin S, Bazile M, Blouin MJ, Topisirovic I, St-Pierre J, Pollak MN. Carbon source and myc expression influence the antiproliferative actions of metformin. Cancer Res. 2012; 72:6257-67.
60. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15:110-21.
61. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18:207-19.
62. Tennant DA, Durán RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010; 10:267-77.
63. Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol. 2014; 42:247-51.
64. Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, Saito K, Kato K, Kato Y, Wakabayashi T, Soga T, Natsume A. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biol. 2014; 35:5911-20.
65. Ciardiello F, Gottardis M, Basolo F, Pepe S, Normanno N, Dickson RB, Bianco AR, Salomon DS. Additive effects of c-erbB-2, c-Ha-ras, and transforming growth factoralpha genes on in vitro transformation of human mammary epithelial cells. Mol Carcinog. 1992; 6:43-52.
66. Giunciuglio D, Culty M, Fassina G, Masiello L, Melchiori A, Paglialunga G, Arand G, Ciardiello F, Basolo F, Thompson EW, et al. Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. Int J Cancer. 1995; 63:815-22.
67. Takeda Y, Totani K, Matsuo I, Ito Y. Chemical approaches toward understanding glycan-mediated protein quality control. Curr Opin Chem Biol. 2009; 13:582-91.
68. Roth J, Zuber C, Park S, Jang I, Lee Y, Kysela KG, Le Fourn V, Santimaria R, Guhl B, Cho JW. Protein N-glycosylation, protein folding, and protein quality control. Mol Cells. 2010; 30:497-506.
69. Katoh T, Takase J, Tani Y, Amamoto R, Aoshima N, Tiemeyer M, Yamamoto K, Ashida H. Deficiency of a-glucosidase I alters glycoprotein glycosylation and lifespan in Caenorhabditis elegans. Glycobiology. 2013; 23:1142-51.
70. Kölker S, Pawlak V, Ahlemeyer B, Okun JG, Hörster F, Mayatepek E, Krieglstein J, Hoffmann GF, Köhr G. NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. Eur J Neurosci. 2002; 16:21-8.
71. Latini A, da Silva CG, Ferreira GC, Schuck PF, Scussiato K, Sarkis JJ, Dutra Filho CS, Wyse AT, Wannmacher CM, Wajner M. Mitochondrial energy metabolism is markedly impaired by D-2-hydroxyglutaric acid in rat tissues. Mol Genet Metab. 2005; 86:188-99.
72. Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, Yan H. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem. 2014; 289:23318-28.
73. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB, Sabatini DM. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014; 508:108-12.
74. Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 2011;10:2350-62.
75. Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C, Yoshioka N, Bucala R, Koike T. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin Cancer Res. 2005; 11:5784-92.
76. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011; 43:869-74.
77. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011; 476:346-50.
78. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2013;493:542-6.
79. Amelio I, Markert EK, Rufini A, Antonov AV, Sayan BS, Tucci P, Agostini M, Mineo TC, Levine AJ, Melino G. p73 regulates serine biosynthesis in cancer. Oncogene. 2014;33:5039-46.
80. Ampuero J, Ranchal I, Nuñez D, Díaz-Herrero Mdel M, Maraver M, del Campo JA, Rojas Á, Camacho I, Figueruela B, Bautista JD, Romero-Gómez M. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One. 2012; 7:e49279.
81. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013; 13:572-83.
82. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013; 342:1242454.
83. Mehrmohamadi M, Liu X, Shestov AA, Locasale JW. Characterization of the usage of the serine metabolic network in human cancer. Cell Rep. 2014; 9:1507-19.
84. Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, Micol V, Joven J, Segura-Carretero A, Menendez JA. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY). 2012; 4:480-98.
85. Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA. 2014; 111:10574-9.
86. Cory JG, Cory AH. Critical roles of glutamine as nitrogen donors in purine and pyrimidine nucleotide synthesis: asparaginase treatment in childhood acute lymphoblastic leukemia. In Vivo. 2006; 20:587-9.
87. Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA, Fredericksen ZS, Kim WR, Gores GJ, Roberts RO, Olson JE, Therneau TM, Roberts LR. Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology. 2013; 57:648-55.
88. Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci USA. 2011; 108:3270-5.
89. Izquierdo-Garcia JL, Viswanath P, Eriksson P, Chaumeil MM, Pieper RO, Phillips JJ, Ronen SM. Metabolic Reprogramming in Mutant IDH1 Glioma Cells. PLoS One. 2015; 10:e0118781.