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Metabolic targeting of malignant tumors: a need for systemic approach

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Abstract

Purpose

Dysregulated metabolism is now recognized as a fundamental hallmark of carcinogenesis inducing aggressive features and additional hallmarks. In this review, well-established metabolic changes displayed by tumors are highlighted in a comprehensive manner and corresponding therapeutical targets are discussed to set up a framework for integrating basic research findings with clinical translation in oncology setting.

Methods

Recent manuscripts of high research impact and relevant to the field from PubMed (2000–2021) have been reviewed for this article.

Results

Metabolic pathway disruption during tumor evolution is a dynamic process potentiating cell survival, dormancy, proliferation and invasion even under dismal conditions. Apart from cancer cells, though, tumor microenvironment has an acting role as extracellular metabolites, pH alterations and stromal cells reciprocally interact with malignant cells, ultimately dictating tumor-promoting responses, disabling anti-tumor immunity and promoting resistance to treatments.

Conclusion

In the field of cancer metabolism, there are several emerging prognostic and therapeutic targets either in the form of gene expression, enzyme activity or metabolites which could be exploited for clinical purposes; both standard-of-care and novel treatments may be evaluated in the context of metabolism rewiring and indeed, synergistic effects between metabolism-targeting and other therapies would be an attractive perspective for further research.

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References

  • Achreja A, Zhao H, Yang L, Yun TH, Marini J, Nagrath D (2017) Exo-MFA-A 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism. Metab Eng 43:156–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24:650–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alexander MS, Wilkes JG, Schroeder SR, Buettner GR, Wagner BA, Du J, Gibson-Corley K, O’Leary BR, Spitz DR, Buatti JM, Berg DJ, Bodeker KL, Vollstedt S, Brown HA, Allen BG, Cullen JJ (2018) Pharmacologic ascorbate reduces radiation-induced normal tissue toxicity and enhances tumor radiosensitization in pancreatic cancer. Can Res 78:6838–6851

    Article  CAS  Google Scholar 

  • Allen E, Mieville P, Warren CM, Saghafinia S, Li L, Peng MW, Hanahan D (2016a) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15:1144–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen EL, Ulanet DB, Pirman D, Mahoney CE, Coco J, Si Y, Chen Y, Huang L, Ren J, Choe S, Clasquin MF, Artin E, Fan ZP, Cianchetta G, Murtie J, Dorsch M, Jin S, Smolen GA (2016b) Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep 17:876–890

    Article  CAS  PubMed  Google Scholar 

  • Amendola CR, Mahaffey JP, Parker SJ, Ahearn IM, Chen WC, Zhou M, Court H, Shi J, Mendoza SL, Morten MJ, Rothenberg E, Gottlieb E, Wadghiri YZ, Possemato R, Hubbard SR, Balmain A, Kimmelman AC, Philips MR (2019) KRAS4A directly regulates hexokinase 1. Nature 576:482–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334:1278–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8:839–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ancey PB, Contat C, Meylan E (2018) Glucose transporters in cancer—from tumor cells to the tumor microenvironment. FEBS J 285:2926–2943

    Article  CAS  PubMed  Google Scholar 

  • Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:1282-1293 e1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Apicella M, Giannoni E, Fiore S, Ferrari KJ, Fernandez-Perez D, Isella C, Granchi C, Minutolo F, Sottile A, Comoglio PM, Medico E, Pietrantonio F, Volante M, Pasini D, Chiarugi P, Giordano S, Corso S (2018) Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab 28:848-865 e846

    Article  CAS  PubMed  Google Scholar 

  • Ariaans G, Jalving M, Vries EG, Jong S (2017) Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells. BMC Cancer 17:232

    Article  PubMed  PubMed Central  Google Scholar 

  • Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, Kelly CJ, Pirovano G, Buffa FM, Hammond EM, Stratford M, Muschel RJ, Higgins GS, McKenna WG (2016) The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun 7:12308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asthana A, Ramakrishnan P, Vicioso Y, Zhang K, Parameswaran R (2018) Hexosamine biosynthetic pathway inhibition leads to AML cell differentiation and cell death. Mol Cancer Ther 17:2226–2237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, Bhattacharyya S, Tumanov S, Allen-Petersen BL, Link J, Kendsersky ND, Vringer E, Schug M, Novo D, Hwang RF, Evans RM, Nixon C, Dorrell C, Morton JP, Norman JC, Sears RC, Kamphorst JJ, Sherman MH (2019) A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov 9:617–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Avnet S, Di Pompo G, Chano T, Errani C, Ibrahim-Hashim A, Gillies RJ, Donati DM, Baldini N (2017) Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-kappaB activation. Int J Cancer 140:1331–1345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, Simmet T, Seufferlein T (2016) PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer 15:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L (2013) The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology 2:e22058

    Article  PubMed  PubMed Central  Google Scholar 

  • Beltinger C (2019) LDHA and LDHB are dispensable for aerobic glycolysis in neuroblastoma cells while promoting their aggressiveness. J Biol Chem 294:66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Haim S, Ell P (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med 50:88–99

    Article  PubMed  Google Scholar 

  • Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY, Maira SM, Moroni C, Lane HA, Hall MN (2018) Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells. Cell Rep 25:3047-3058 e3044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120

    Article  CAS  PubMed  Google Scholar 

  • Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, Pinnick KE, Wigfield S, Buffa FM, Li JL, Zhang Q, Wakelam MJO, Karpe F, Schulze A, Harris AL (2014) Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep 9:349–365

    Article  CAS  PubMed  Google Scholar 

  • Bhanot H, Reddy MM, Nonami A, Weisberg EL, Bonal D, Kirschmeier PT, Salgia S, Podar K, Galinsky I, Chowdary TK, Neuberg D, Tonon G, Stone RM, Asara J, Griffin JD, Sattler M (2015) Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells. Leukemia 29:1555–1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, Pfeffer U, Sambuceti G, Pistoia V, Raffaghello L, Longo VD (2015) Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget 6:11806–11819

    Article  PubMed  PubMed Central  Google Scholar 

  • Birkenmeier K, Drose S, Wittig I, Winkelmann R, Kafer V, Doring C, Hartmann S, Wenz T, Reichert AS, Brandt U, Hansmann ML (2016) Hodgkin and Reed–Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. Int J Cancer 138:2231–2246

    Article  CAS  PubMed  Google Scholar 

  • Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, Aranda Lopez P, Hahlbrock J, Muth S, Endo S, Pektor S, Brand A, Renner K, Popp V, Gerlach K, Vogel D, Lueckel C, Arnold-Schild D, Pouyssegur J, Kreutz M, Huber M, Koenig J, Weigmann B, Probst HC, von Stebut E, Becker C, Schild H, Schmitt E, Bopp T (2018) Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol 19:1319–1329

    Article  CAS  PubMed  Google Scholar 

  • Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671

    Article  CAS  PubMed  Google Scholar 

  • Brauer HA, Makowski L, Hoadley KA, Casbas-Hernandez P, Lang LJ, Roman-Perez E, D’Arcy M, Freemerman AJ, Perou CM, Troester MA (2013) Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer. Clin Cancer Res 19:571–585

    Article  CAS  PubMed  Google Scholar 

  • Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K, Kilian M, Neftel C, Uhlig S, Kessler T, von Landenberg A, Berghoff AS, Marsh K, Steadman M, Zhu D, Nicolay B, Wiestler B, Breckwoldt MO, Al-Ali R, Karcher-Bausch S, Bozza M, Oezen I, Kramer M, Meyer J, Habel A, Eisel J, Poschet G, Weller M, Preusser M, Nadji-Ohl M, Thon N, Burger MC, Harter PN, Ratliff M, Harbottle R, Benner A, Schrimpf D, Okun J, Herold-Mende C, Turcan S, Kaulfuss S, Hess-Stumpp H, Bieback K, Cahill DP, Plate KH, Hanggi D, Dorsch M, Suva ML, Niemeyer BA, von Deimling A, Wick W, Platten M (2018) Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med 24:1192–1203

    Article  CAS  PubMed  Google Scholar 

  • Caffa I, Longo VD, Nencioni A (2015) Fasting plus tyrosine kinase inhibitors in cancer. Aging 7:1026–1027

    Article  PubMed  PubMed Central  Google Scholar 

  • Caffa I, Spagnolo V, Vernieri C, Valdemarin F, Becherini P, Wei M, Brandhorst S, Zucal C, Driehuis E, Ferrando L, Piacente F, Tagliafico A, Cilli M, Mastracci L, Vellone VG, Piazza S, Cremonini AL, Gradaschi R, Mantero C, Passalacqua M, Ballestrero A, Zoppoli G, Cea M, Arrighi A, Odetti P, Monacelli F, Salvadori G, Cortellino S, Clevers H, De Braud F, Sukkar SG, Provenzani A, Longo VD, Nencioni A (2020) Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 583:620–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquiere B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, Carmeliet P (2016) Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:968–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmona-Fontaine C, Deforet M, Akkari L, Thompson CB, Joyce JA, Xavier JB (2017) Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci USA 114:2934–2939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, Polak K, Tondera D, Gounarides J, Yin H, Zhou F, Green MR, Chen L, Monti S, Marto JA, Shipp MA, Danial NN (2012) Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22:547–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185:1037–1044

    Article  CAS  PubMed  Google Scholar 

  • Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M (2014) Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33:1743–1754

    Article  CAS  PubMed  Google Scholar 

  • Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chanmee T, Ontong P, Izumikawa T, Higashide M, Mochizuki N, Chokchaitaweesuk C, Khansai M, Nakajima K, Kakizaki I, Kongtawelert P, Taniguchi N, Itano N (2016) Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling. J Biol Chem 291:24105–24120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M (2008) Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA 105:11105–11109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen WL, Jin X, Wang M, Liu D, Luo Q, Tian H, Cai L, Meng L, Bi R, Wang L, Xie X, Yu G, Li L, Dong C, Cai Q, Jia W, Wei W, Jia L (2020) GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight 5:1

    Article  Google Scholar 

  • Chiavarina B, Whitaker-Menezes D, Martinez-Outschoorn UE, Witkiewicz AK, Birbe R, Howell A, Pestell RG, Smith J, Daniel R, Sotgia F, Lisanti MP (2011) Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol Ther 12:1101–1113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi SY, Xue H, Wu R, Fazli L, Lin D, Collins CC, Gleave ME, Gout PW, Wang Y (2016) The MCT4 gene: a novel, potential target for therapy of advanced prostate cancer. Clin Cancer Res 22:2721–2733

    Article  CAS  PubMed  Google Scholar 

  • Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233

    Article  CAS  PubMed  Google Scholar 

  • Chu D, Zhu S, Li J, Ji G, Wang W, Wu G, Zheng J (2014) CD147 expression in human gastric cancer is associated with tumor recurrence and prognosis. PLoS ONE 9:e101027

    Article  PubMed  PubMed Central  Google Scholar 

  • Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, Ng V, Xia B, Witkowski MT, Mitchell-Flack M, Grillo I, Bakogianni S, Ndiaye-Lobry D, Martin MT, Guillamot M, Banh RS, Xu M, Figueroa ME, Dickins RA, Abdel-Wahab O, Park CY, Tsirigos A, Neel BG, Aifantis I (2017) Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170:1079-1095 e1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corbet C, Feron O (2017) Tumour acidosis: from the passenger to the driver’s seat. Nat Rev Cancer 17:577–593

    Article  CAS  PubMed  Google Scholar 

  • Corbet C, Draoui N, Polet F, Pinto A, Drozak X, Riant O, Feron O (2014) The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Can Res 74:5507–5519

    Article  CAS  Google Scholar 

  • Corbet C, Pinto A, Martherus R, Santiago de Jesus JP, Polet F, Feron O (2016) Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metab 24:311–323

    Article  CAS  PubMed  Google Scholar 

  • Corbet C, Bastien E, Santiago de Jesus JP, Dierge E, Martherus R, Vander Linden C, Doix B, Degavre C, Guilbaud C, Petit L, Michiels C, Dessy C, Larondelle Y, Feron O (2020) TGFbeta2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nat Commun 11:454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cui Y, Xing P, Wang Y, Liu M, Qiu L, Ying G, Li B (2017) NADPH accumulation is responsible for apoptosis in breast cancer cells induced by fatty acid synthase inhibition. Oncotarget 8:32576–32585

    Article  PubMed  PubMed Central  Google Scholar 

  • Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, Leiby B, Cognetti DM, Sotgia F, Lisanti MP, Martinez-Outschoorn UE (2013) Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 12:1371–1384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH (1997) Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem 272:17269–17275

    Article  CAS  PubMed  Google Scholar 

  • DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446

    Article  PubMed  PubMed Central  Google Scholar 

  • Diepart C, Karroum O, Magat J, Feron O, Verrax J, Calderon PB, Gregoire V, Leveque P, Stockis J, Dauguet N, Jordan BF, Gallez B (2012) Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors. Can Res 72:482–490

    Article  CAS  Google Scholar 

  • Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, Hellerbrand C, Kastenberger M, Kunz-Schughart LA, Oefner PJ, Andreesen R, Gottfried E, Kreutz MP (2010) Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 184:1200–1209

    Article  CAS  PubMed  Google Scholar 

  • Doherty JR, Yang C, Scott KE, Cameron MD, Fallahi M, Li W, Hall MA, Amelio AL, Mishra JK, Li F, Tortosa M, Genau HM, Rounbehler RJ, Lu Y, Dang CV, Kumar KG, Butler AA, Bannister TD, Hooper AT, Unsal-Kacmaz K, Roush WR, Cleveland JL (2014) Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Can Res 74:908–920

    Article  CAS  Google Scholar 

  • Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ (2010) Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res 16:509–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du J, Cieslak JA 3rd, Welsh JL, Sibenaller ZA, Allen BG, Wagner BA, Kalen AL, Doskey CM, Strother RK, Button AM, Mott SL, Smith B, Tsai S, Mezhir J, Goswami PC, Spitz DR, Buettner GR, Cullen JJ (2015) Pharmacological ascorbate radiosensitizes pancreatic cancer. Can Res 75:3314–3326

    Article  CAS  Google Scholar 

  • Elgendy M, Ciro M, Hosseini A, Weiszmann J, Mazzarella L, Ferrari E, Cazzoli R, Curigliano G, DeCensi A, Bonanni B, Budillon A, Pelicci PG, Janssens V, Ogris M, Baccarini M, Lanfrancone L, Weckwerth W, Foiani M, Minucci S (2019) Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3beta-MCL-1 axis. Cancer Cell 35:798-815 e795

    Article  CAS  PubMed  Google Scholar 

  • Ericksen RE, Lim SL, McDonnell E, Shuen WH, Vadiveloo M, White PJ, Ding Z, Kwok R, Lee P, Radda GK, Toh HC, Hirschey MD, Han W (2019) Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression. Cell Metab 29:1151-1165 e1156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, Chen Q (2011) Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radical Biol Med 50:1610–1619

    Article  CAS  Google Scholar 

  • Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ (2013) Acidity generated by the tumor microenvironment drives local invasion. Can Res 73:1524–1535

    Article  CAS  Google Scholar 

  • Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, Li H, Huet G, Yuan Q, Wigal T, Butt Y, Ni M, Torrealba J, Oliver D, Lenkinski RE, Malloy CR, Wachsmann JW, Young JD, Kernstine K, DeBerardinis RJ (2017) Lactate metabolism in human lung tumors. Cell 171:358-371 e359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, Picci P, Gambarotti M, Avnet S, Baldini N, Fais S (2013) Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med 11:268

    Article  PubMed  PubMed Central  Google Scholar 

  • Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, Chiarugi P (2012) Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Can Res 72:5130–5140

    Article  CAS  Google Scholar 

  • Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2016) Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget 7:34084–34099

    Article  PubMed  PubMed Central  Google Scholar 

  • Galan-Cobo A, Sitthideatphaiboon P, Qu X, Poteete A, Pisegna MA, Tong P, Chen PH, Boroughs LK, Rodriguez MLM, Zhang W, Parlati F, Wang J, Gandhi V, Skoulidis F, DeBerardinis RJ, Minna JD, Heymach JV (2019) LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Can Res 79:3251–3267

    Article  CAS  Google Scholar 

  • Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP Jr, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW (2019) Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572:397–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Bermudez J, Baudrier L, La K, Zhu XG, Fidelin J, Sviderskiy VO, Papagiannakopoulos T, Molina H, Snuderl M, Lewis CA, Possemato RL, Birsoy K (2018) Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat Cell Biol 20:775–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ (2006) Acid-mediated tumor invasion: a multidisciplinary study. Can Res 66:5216–5223

    Article  CAS  Google Scholar 

  • Gaude E, Frezza C (2016) Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat Commun 7:13041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, Zamboni N, Sallusto F, Lanzavecchia A (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167:829-842 e813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Girgis H, Masui O, White NM, Scorilas A, Rotondo F, Seivwright A, Gabril M, Filter ER, Girgis AH, Bjarnason GA, Jewett MA, Evans A, Al-Haddad S, Siu KM, Yousef GM (2014) Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer 13:101

    Article  PubMed  PubMed Central  Google Scholar 

  • Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discovery 12:931–947

    Article  CAS  PubMed  Google Scholar 

  • Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, Janes JR, Laidig GJ, Lewis ER, Li J, Mackinnon AL, Parlati F, Rodriguez ML, Shwonek PJ, Sjogren EB, Stanton TF, Wang T, Yang J, Zhao F, Bennett MK (2014) Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 13:890–901

    Article  CAS  PubMed  Google Scholar 

  • Gu Z, Liu Y, Cai F, Patrick M, Zmajkovic J, Cao H, Zhang Y, Tasdogan A, Chen M, Qi L, Liu X, Li K, Lyu J, Dickerson KE, Chen W, Ni M, Merritt ME, Morrison SJ, Skoda RC, DeBerardinis RJ, Xu J (2019) Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov 9:1228–1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guillaumond F, Leca J, Olivares O, Lavaut MN, Vidal N, Berthezene P, Dusetti NJ, Loncle C, Calvo E, Turrini O, Iovanna JL, Tomasini R, Vasseur S (2013) Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci USA 110:3919–3924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta A, Ajith A, Singh S, Panday RK, Samaiya A, Shukla S (2018) PAK2-c-Myc-PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect. Cell Death Dis 9:825

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamann I, Krys D, Glubrecht D, Bouvet V, Marshall A, Vos L, Mackey JR, Wuest M, Wuest F (2018) Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer-effects of hypoxia. FASEB J 32:5104–5118

    Article  CAS  PubMed  Google Scholar 

  • Hao Y, Samuels Y, Li Q, Krokowski D, Guan BJ, Wang C, Jin Z, Dong B, Cao B, Feng X, Xiang M, Xu C, Fink S, Meropol NJ, Xu Y, Conlon RA, Markowitz S, Kinzler KW, Velculescu VE, Brunengraber H, Willis JE, LaFramboise T, Hatzoglou M, Zhang GF, Vogelstein B, Wang Z (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, Tayyari F, McSkimming D, Kannan N, Tojo A, Edison AS, Ito T (2017) Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 545:500–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8:311–321

    Article  CAS  PubMed  Google Scholar 

  • Hefetz-Sela S, Scherer PE (2013) Adipocytes: impact on tumor growth and potential sites for therapeutic intervention. Pharmacol Ther 138:197–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hensley CT, Wasti AT, DeBerardinis RJ (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Investig 123:3678–3684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernandez-Resendiz I, Gallardo-Perez JC, Lopez-Macay A, Robledo-Cadena DX, Garcia-Villa E, Gariglio P, Saavedra E, Moreno-Sanchez R, Rodriguez-Enriquez S (2019) Mutant p53(R248Q) downregulates oxidative phosphorylation and upregulates glycolysis under normoxia and hypoxia in human cervix cancer cells. J Cell Physiol 234:5524–5536

    Article  CAS  PubMed  Google Scholar 

  • Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr (2008) Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 19:1969–1974

    Article  CAS  PubMed  Google Scholar 

  • Hong CS, Graham NA, Gu W, Espindola Camacho C, Mah V, Maresh EL, Alavi M, Bagryanova L, Krotee PAL, Gardner BK, Behbahan IS, Horvath S, Chia D, Mellinghoff IK, Hurvitz SA, Dubinett SM, Critchlow SE, Kurdistani SK, Goodglick L, Braas D, Graeber TG, Christofk HR (2016) MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4. Cell Rep 14:1590–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu YL, Hung JY, Chiang SY, Jian SF, Wu CY, Lin YS, Tsai YM, Chou SH, Tsai MJ, Kuo PL (2016) Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7:27584–27598

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Lu W, Chen G, Wang P, Chen Z, Zhou Y, Ogasawara M, Trachootham D, Feng L, Pelicano H, Chiao PJ, Keating MJ, Garcia-Manero G, Huang P (2012) K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 22:399–412

    Article  CAS  PubMed  Google Scholar 

  • Huang X, Li X, Xie X, Ye F, Chen B, Song C, Tang H, Xie X (2016) High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer. Breast 30:39–46

    Article  PubMed  Google Scholar 

  • Hulea L, Gravel SP, Morita M, Cargnello M, Uchenunu O, Im YK, Lehuede C, Ma EH, Leibovitch M, McLaughlan S, Blouin MJ, Parisotto M, Papavasiliou V, Lavoie C, Larsson O, Ohh M, Ferreira T, Greenwood C, Bridon G, Avizonis D, Ferbeyre G, Siegel P, Jones RG, Muller W, Ursini-Siegel J, St-Pierre J, Pollak M, Topisirovic I (2018) Translational and HIF-1alpha-dependent metabolic reprogramming underpin metabolic plasticity and responses to kinase inhibitors and biguanides. Cell Metab 28:817-832 e818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hulikova A, Black N, Hsia LT, Wilding J, Bodmer WF, Swietach P (2016) Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid. Proc Natl Acad Sci USA 113:E5344-5353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iida Y, Aoki K, Asakura T, Ueda K, Yanaihara N, Takakura S, Yamada K, Okamoto A, Tanaka T, Ohkawa K (2012) Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma. Int J Oncol 40:2122–2130

    CAS  PubMed  Google Scholar 

  • Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664

    Article  CAS  PubMed  Google Scholar 

  • Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden MG (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409

    Article  CAS  PubMed  Google Scholar 

  • Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M, Poulain L, Hospital MA, Sujobert P, Joseph L, Chapuis N, Lacombe C, Moura IC, Demo S, Sarry JE, Recher C, Mayeux P, Tamburini J, Bouscary D (2015) Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 126:1346–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeon H, Kim JH, Lee E, Jang YJ, Son JE, Kwon JY, Lim TG, Kim S, Park JH, Kim JE, Lee KW (2016) Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo. Oncotarget 7:67223–67234

    Article  PubMed  PubMed Central  Google Scholar 

  • Jia D, Lu M, Jung KH, Park JH, Yu L, Onuchic JN, Kaipparettu BA, Levine H (2019) Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways. Proc Natl Acad Sci USA 116:3909–3918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, Boggon TJ, Jin P, Yi H, Wright ER, Duong D, Seyfried NT, Egnatchik R, DeBerardinis RJ, Magliocca KR, He C, Arellano ML, Khoury HJ, Shin DM, Khuri FR, Kang S (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jing Z, Heng W, Aiping D, Yafei Q, Shulan Z (2013) Expression and clinical significance of phosphoglycerate dehydrogenase and squamous cell carcinoma antigen in cervical cancer. Int J Gynecol Cancer 23:1465–1469

    Article  PubMed  Google Scholar 

  • John S, Weiss JN, Ribalet B (2011) Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE 6:e17674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, Chung PE, Pellecchia G, Fell VL, Bae S, Muthuswamy L, Datti A, Egan SE, Jiang Z, Leone G, Bader GD, Schimmer A, Zacksenhaus E (2016) RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J Clin Investig 126:3739–3757

    Article  PubMed  PubMed Central  Google Scholar 

  • Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, Thompson CB, Rabinowitz JD (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA 110:8882–8887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katheder NS, Khezri R, O’Farrell F, Schultz SW, Jain A, Rahman MM, Schink KO, Theodossiou TA, Johansen T, Juhasz G, Bilder D, Brech A, Stenmark H, Rusten TE (2017) Microenvironmental autophagy promotes tumour growth. Nature 541:417–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawaguchi K, Miyake K, Han Q, Li S, Tan Y, Igarashi K, Lwin TM, Higuchi T, Kiyuna T, Miyake M, Oshiro H, Bouvet M, Unno M, Hoffman RM (2018) Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer. Cell Cycle 17:868–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kendrick AA, Schafer J, Dzieciatkowska M, Nemkov T, D’Alessandro A, Neelakantan D, Ford HL, Pearson CG, Weekes CD, Hansen KC, Eisenmesser EZ (2017) CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming. Oncotarget 8:6742–6762

    Article  PubMed  Google Scholar 

  • Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP (2016) Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531:110–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khacho M, Tarabay M, Patten D, Khacho P, MacLaurin JG, Guadagno J, Bergeron R, Cregan SP, Harper ME, Park DS, Slack RS (2014) Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival. Nat Commun 5:3550

    Article  PubMed  Google Scholar 

  • Kim YH, Jeong DC, Pak K, Han ME, Kim JY, Liangwen L, Kim HJ, Kim TW, Kim TH, Hyun DW, Oh SO (2017) SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget 8:68381–68392

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim HK, Lee I, Bang H, Kim HC, Lee WY, Yun SH, Lee J, Lee SJ, Park YS, Kim KM, Kang WK (2018) MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis. Mol Cancer Ther 17:838–848

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Yu L, Chen W, Xu Y, Wu M, Todorova D, Tang Q, Feng B, Jiang L, He J, Chen G, Fu X, Xu Y (2019) Wild-Type p53 promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation. Cancer Cell 35:191-203 e198

    Article  CAS  PubMed  Google Scholar 

  • Klotz LO, Sanchez-Ramos C, Prieto-Arroyo I, Urbanek P, Steinbrenner H, Monsalve M (2015) Redox regulation of FoxO transcription factors. Redox Biol 6:51–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, Taylor N (2015) Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal 8:ra97

    Article  PubMed  Google Scholar 

  • Knott SRV, Wagenblast E, Khan S, Kim SY, Soto M, Wagner M, Turgeon MO, Fish L, Erard N, Gable AL, Maceli AR, Dickopf S, Papachristou EK, D’Santos CS, Carey LA, Wilkinson JE, Harrell JC, Perou CM, Goodarzi H, Poulogiannis G, Hannon GJ (2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554:378–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kruiswijk F, Labuschagne CF, Vousden KH (2015) p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16:393–405

    Article  CAS  PubMed  Google Scholar 

  • Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL, Helgason GV, Gottlieb E (2017) Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 23:1234–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD (2014) Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 7:1248–1258

    Article  CAS  PubMed  Google Scholar 

  • Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, Sundaresan S, Nieman KM, Pascual G, Benitah SA, Montag A, Yamada SD, Abumrad NA, Lengyel E (2018) Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37:2285–2301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O’Dwyer KM, Liesveld JL, Brookes PS, Becker MW, Jordan CT (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12:329–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larman TC, DePalma SR, Hadjipanayis AG, Cancer Genome Atlas Research N, Protopopov A, Zhang J, Gabriel SB, Chin L, Seidman CE, Kucherlapati R, Seidman JG (2012) Spectrum of somatic mitochondrial mutations in five cancers. Proc Natl Acad Sci USA 109:14087–14091

  • Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 107:2037–2042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, Hwang D, Cohen P, Bianchi G, Longo VD (2010) Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Can Res 70:1564–1572

    Article  CAS  Google Scholar 

  • Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD (2012a) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 4:124ra127

    Article  Google Scholar 

  • Lee C, Raffaghello L, Longo VD (2012b) Starvation, detoxification, and multidrug resistance in cancer therapy. Drug Resist Updates: Rev Comment Antimicrob Anticancer Chemother 15:114–122

    Article  CAS  Google Scholar 

  • Li Z, Wang Z, Tang Y, Lu X, Chen J, Dong Y, Wu B, Wang C, Yang L, Guo Z, Xue M, Lu S, Wei W, Shi Q (2019) Liquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics. Nat Commun 10:3856

    Article  PubMed  PubMed Central  Google Scholar 

  • Li JT, Yin M, Wang D, Wang J, Lei MZ, Zhang Y, Liu Y, Zhang L, Zou SW, Hu LP, Zhang ZG, Wang YP, Wen WY, Lu HJ, Chen ZJ, Su D, Lei QY (2020) BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma. Nat Cell Biol 22:167–174

    Article  CAS  PubMed  Google Scholar 

  • Liang J, Cao R, Zhang Y, Xia Y, Zheng Y, Li X, Wang L, Yang W, Lu Z (2016) PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nat Commun 7:12431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang J, Cao R, Wang X, Zhang Y, Wang P, Gao H, Li C, Yang F, Zeng R, Wei P, Li D, Li W, Yang W (2017) Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res 27:329–351

    Article  CAS  PubMed  Google Scholar 

  • Lim SC, Carey KT, McKenzie M (2015) Anti-cancer analogues ME-143 and ME-344 exert toxicity by directly inhibiting mitochondrial NADH: ubiquinone oxidoreductase (Complex I). Am J Cancer Res 5:689–701

    PubMed  PubMed Central  Google Scholar 

  • Linster CL, Van Schaftingen E (2007) Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J 274:1–22

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Guo S, Li Q, Yang L, Xia Z, Zhang L, Huang Z, Zhang N (2013) Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J Neurooncol 111:245–255

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Liu N, Cheng Y, Jin W, Zhang P, Wang X, Yang H, Xu X, Wang Z, Tu Y (2017) Hexokinase 2 (HK2), the tumor promoter in glioma, is downregulated by miR-218/Bmi1 pathway. PLoS ONE 12:e0189353

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu M, Tsang JYS, Lee M, Ni YB, Chan SK, Cheung SY, Hu J, Hu H, Tse GMK (2018) CD147 expression is associated with poor overall survival in chemotherapy treated triple-negative breast cancer. J Clin Pathol 71:1007–1014

    Article  CAS  PubMed  Google Scholar 

  • 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 (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43:869–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, Patel N, Teoh EJ, Gleeson F, Bradley K, Wigfield S, Zois C, McGowan DR, Ah-See ML, Thompson AM, Sharma A, Bidaut L, Pollak M, Roy PG, Karpe F, James T, English R, Adams RF, Campo L, Ayers L, Snell C, Roxanis I, Frezza C, Fenwick JD, Buffa FM, Harris AL (2018) Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab 28:679-688 e674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu C, Venneti S, Akalin A, Fang F, Ward PS, Dematteo RG, Intlekofer AM, Chen C, Ye J, Hameed M, Nafa K, Agaram NP, Cross JR, Khanin R, Mason CE, Healey JH, Lowe SW, Schwartz GK, Melnick A, Thompson CB (2013) Induction of sarcomas by mutant IDH2. Genes Dev 27:1986–1998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F, Federici C, Iessi E, Parmiani G, Arancia G, Belardelli F, Fais S (2004) Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 96:1702–1713

    Article  CAS  PubMed  Google Scholar 

  • Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, Wenger RH, Ohta A, Sitkovsky M (2006) Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177:4962–4965

    Article  CAS  PubMed  Google Scholar 

  • Lukey MJ, Cluntun AA, Katt WP, Lin MJ, Druso JE, Ramachandran S, Erickson JW, Le HH, Wang ZE, Blank B, Greene KS, Cerione RA (2019) Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer. Cell Rep 29:76-88 e77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo M, Shang L, Brooks MD, Jiagge E, Zhu Y, Buschhaus JM, Conley S, Fath MA, Davis A, Gheordunescu E, Wang Y, Harouaka R, Lozier A, Triner D, McDermott S, Merajver SD, Luker GD, Spitz DR, Wicha MS (2018) Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab 28:69-86 e66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q (2014) High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 6:222ra218

    Article  Google Scholar 

  • Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, Mainolfi N, Suri V, Guak H, Balmer ML, Verway MJ, Raissi TC, Tsui H, Boukhaled G, Henriques da Costa S, Frezza C, Krawczyk CM, Friedman A, Manfredi M, Richer MJ, Hess C, Jones RG (2017a) Serine is an essential metabolite for effector T cell expansion. Cell Metab 25:345–357

    Article  CAS  PubMed  Google Scholar 

  • Ma MKF, Lau EYT, Leung DHW, Lo J, Ho NPY, Cheng LKW, Ma S, Lin CH, Copland JA, Ding J, Lo RCL, Ng IOL, Lee TKW (2017b) Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation. J Hepatol 67:979–990

    Article  CAS  PubMed  Google Scholar 

  • Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH (2013) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493:542–546

    Article  CAS  PubMed  Google Scholar 

  • Maddocks OD, Labuschagne CF, Adams PD, Vousden KH (2016) Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell 61:210–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, Blagih J, Vincent DF, Campbell KJ, Ceteci F, Sansom OJ, Blyth K, Vousden KH (2017) Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544:372–376

    Article  CAS  PubMed  Google Scholar 

  • Markert EK, Vazquez A (2015) Mathematical models of cancer metabolism. Cancer Metab 3:14

    Article  PubMed  PubMed Central  Google Scholar 

  • Martinez-Outschoorn UE, Lisanti MP, Sotgia F (2014) Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol 25:47–60

    Article  CAS  PubMed  Google Scholar 

  • Mattaini KR, Sullivan MR, Vander Heiden MG (2016) The importance of serine metabolism in cancer. J Cell Biol 214:249–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, Lau AN, Ji BW, Dixit PD, Hosios AM, Muir A, Chin CR, Freinkman E, Jacks T, Wolpin BM, Vitkup D, Vander Heiden MG (2016) Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353:1161–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCleland ML, Adler AS, Deming L, Cosino E, Lee L, Blackwood EM, Solon M, Tao J, Li L, Shames D, Jackson E, Forrest WF, Firestein R (2013) Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin Cancer Res 19:773–784

    Article  CAS  PubMed  Google Scholar 

  • Menendez JA, Lupu R (2017) Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets 21:1001–1016

    Article  CAS  PubMed  Google Scholar 

  • Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R (2004) Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA 101:10715–10720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384

    Article  PubMed  PubMed Central  Google Scholar 

  • Misra S, Boylan M, Selvam A, Spallholz JE, Bjornstedt M (2015) Redox-active selenium compounds—from toxicity and cell death to cancer treatment. Nutrients 7:3536–3556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, Pillai MV, Newberg AB, Deshmukh S, Levine M (2012) Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE 7:e29794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2011) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:385–388

    Article  PubMed  PubMed Central  Google Scholar 

  • Muranen T, Iwanicki MP, Curry NL, Hwang J, DuBois CD, Coloff JL, Hitchcock DS, Clish CB, Brugge JS, Kalaany NY (2017) Starved epithelial cells uptake extracellular matrix for survival. Nat Commun 8:13989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy DJ, Junttila MR, Pouyet L, Karnezis A, Shchors K, Bui DA, Brown-Swigart L, Johnson L, Evan GI (2008) Distinct thresholds govern Myc’s biological output in vivo. Cancer Cell 14:447–457

    Article  CAS  PubMed  Google Scholar 

  • Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navarro P, Bueno MJ, Zagorac I, Mondejar T, Sanchez J, Mouron S, Munoz J, Gomez-Lopez G, Jimenez-Renard V, Mulero F, Chandel NS, Quintela-Fandino M (2016) Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics. Cell Rep 15:2705–2718

    Article  CAS  PubMed  Google Scholar 

  • Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discovery 10:767–777

    Article  CAS  PubMed  Google Scholar 

  • Olivares O, Mayers JR, Gouirand V, Torrence ME, Gicquel T, Borge L, Lac S, Roques J, Lavaut MN, Berthezene P, Rubis M, Secq V, Garcia S, Moutardier V, Lombardo D, Iovanna JL, Tomasini R, Guillaumond F, Vander Heiden MG, Vasseur S (2017) Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun 8:16031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olzmann JA, Carvalho P (2019) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 20:137–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203

    Article  CAS  PubMed  Google Scholar 

  • Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, Possemato R, Chen WW, Sullivan LB, Fiske BP, Cho S, Freinkman E, Birsoy K, Abu-Remaileh M, Shaul YD, Liu CM, Zhou M, Koh MJ, Chung H, Davidson SM, Luengo A, Wang AQ, Xu X, Yasgar A, Liu L, Rai G, Westover KD, Vander Heiden MG, Shen M, Gray NS, Boxer MB, Sabatini DM (2016) A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol 12:452–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park JK, Coffey NJ, Limoges A, Le A (2018) The heterogeneity of lipid metabolism in cancer. Adv Exp Med Biol 1063:33–55

    Article  CAS  PubMed  Google Scholar 

  • Park JH, Zhao M, Han Q, Sun Y, Higuchi T, Sugisawa N, Yamamoto J, Singh SR, Clary B, Bouvet M, Hoffman RM (2019) Efficacy of oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil on primary colon cancer in a patient-derived orthotopic xenograft mouse model. Biochem Biophys Res Commun 518:306–310

    Article  CAS  PubMed  Google Scholar 

  • Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey B, Hay N (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peck B, Schulze A (2016) Lipid desaturation—The next step in targeting lipogenesis in cancer? FEBS J 283:2767–2778

    Article  CAS  PubMed  Google Scholar 

  • Peeters K, Van Leemputte F, Fischer B, Bonini BM, Quezada H, Tsytlonok M, Haesen D, Vanthienen W, Bernardes N, Gonzalez-Blas CB, Janssens V, Tompa P, Versees W, Thevelein JM (2017) Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras. Nat Commun 8:922

    Article  PubMed  PubMed Central  Google Scholar 

  • Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouyssegur J, Mazure NM (2012) Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front Oncol 2:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Peppicelli S, Bianchini F, Toti A, Laurenzana A, Fibbi G, Calorini L (2015) Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression. Cell Cycle 14:3088–3100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petrul HM, Schatz CA, Kopitz CC, Adnane L, McCabe TJ, Trail P, Ha S, Chang YS, Voznesensky A, Ranges G, Tamburini PP (2012) Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79-4620 targeting human carbonic anhydrase 9. Mol Cancer Ther 11:340–349

    Article  CAS  PubMed  Google Scholar 

  • Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mule JJ, Ibrahim-Hashim A, Gillies RJ (2016) Neutralization of tumor acidity improves antitumor responses to immunotherapy. Can Res 76:1381–1390

    Article  CAS  Google Scholar 

  • Pisanu ME, Noto A, De Vitis C, Morrone S, Scognamiglio G, Botti G, Venuta F, Diso D, Jakopin Z, Padula F, Ricci A, Mariotta S, Giovagnoli MR, Giarnieri E, Amelio I, Agostini M, Melino G, Ciliberto G, Mancini R (2017) Blockade of stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Lett 406:93–104

    Article  CAS  PubMed  Google Scholar 

  • Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess C, Christofori G (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15:1161–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polanski R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ (2014) Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res 20:926–937

    Article  CAS  PubMed  Google Scholar 

  • 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 (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476:346–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 23:7315–7328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricciardiello F, Votta G, Palorini R, Raccagni I, Brunelli L, Paiotta A, Tinelli F, D’Orazio G, Valtorta S, De Gioia L, Pastorelli R, Moresco RM, La Ferla B, Chiaradonna F (2018) Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis. Cell Death Dis 9:377

    Article  PubMed  PubMed Central  Google Scholar 

  • Roberts DJ, Miyamoto S (2015) Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ 22:364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robey RB, Hay N (2006) Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25:4683–4696

    Article  CAS  PubMed  Google Scholar 

  • Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ (2009) Bicarbonate increases tumor pH and inhibits spontaneous metastases. Can Res 69:2260–2268

    Article  CAS  Google Scholar 

  • Rohani N, Hao L, Alexis MS, Joughin BA, Krismer K, Moufarrej MN, Soltis AR, Lauffenburger DA, Yaffe MB, Burge CB, Bhatia SN, Gertler FB (2019) Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Can Res 79:1952–1966

    Article  CAS  Google Scholar 

  • 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 (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rojo de la Vega M, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34:21–43

    Article  CAS  PubMed  Google Scholar 

  • Rouleau L, Antony AN, Bisetto S, Newberg A, Doria C, Levine M, Monti DA, Hoek JB (2016) Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: new insights into ascorbate cytotoxicity. Free Radical Biol Med 95:308–322

    Article  CAS  Google Scholar 

  • Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, Van Veldhoven PP, Waltregny D, Daniels VW, Machiels J, Vanderhoydonc F, Smans K, Waelkens E, Verhoeven G, Swinnen JV (2010) De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Can Res 70:8117–8126

    Article  CAS  Google Scholar 

  • Sabharwal SS, Schumacker PT (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 14:709–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satoh K, Yachida S, Sugimoto M, Oshima M, Nakagawa T, Akamoto S, Tabata S, Saitoh K, Kato K, Sato S, Igarashi K, Aizawa Y, Kajino-Sakamoto R, Kojima Y, Fujishita T, Enomoto A, Hirayama A, Ishikawa T, Taketo MM, Kushida Y, Haba R, Okano K, Tomita M, Suzuki Y, Fukuda S, Aoki M, Soga T (2017) Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. Proc Natl Acad Sci USA 114:E7697–E7706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, Moatamed NA, Huang J, Koepsell H, Barrio JR, Wright EM (2015) Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci USA 112:E4111-4119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS (2009) Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461:109–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453-462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Kauffman EPS, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG (2017a) O2(−) and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 32:268

    Article  CAS  PubMed  Google Scholar 

  • Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Shanahan Kauffman EP, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG (2017b) O2(−) and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 31:487-500 e488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E (2015) Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27:57–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, Shaw RJ (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah S, Carriveau WJ, Li J, Campbell SL, Kopinski PK, Lim HW, Daurio N, Trefely S, Won KJ, Wallace DC, Koumenis C, Mancuso A, Wellen KE (2016) Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 7:43713–43730

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen L, O’Shea JM, Kaadige MR, Cunha S, Wilde BR, Cohen AL, Welm AL, Ayer DE (2015) Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci USA 112:5425–5430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295:E242-253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, Oster ZH, Sacker DF, Shiue CY, Turner H, Wan CN, Wolf AP, Zabinski SV (1980) A fluorinated glucose analog, 2-fluoro-2-deoxy-d-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med 21:670–675

    CAS  PubMed  Google Scholar 

  • Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 118:3930–3942

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, Asara JM, Evans RM, Cantley LC, Lyssiotis CA, Kimmelman AC (2016) Erratum: Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 540:150

    Article  CAS  PubMed  Google Scholar 

  • Stephenson CM, Levin RD, Spector T, Lis CG (2013) Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol 72:139–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stine ZE, Schug ZT, Salvino JM, Dang CV (2022) Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discovery 21:141–162

    Article  CAS  PubMed  Google Scholar 

  • Stolwijk JM, Garje R, Sieren JC, Buettner GR, Zakharia Y (2020) Understanding the redox biology of selenium in the search of targeted cancer therapies. Antioxidants 9:1

    Article  Google Scholar 

  • Su X, Abumrad NA (2009) Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 20:72–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su C, Li H, Gao W (2018) GLUT5 increases fructose utilization and promotes tumor progression in glioma. Biochem Biophys Res Commun 500:462–469

    Article  CAS  PubMed  Google Scholar 

  • Sullivan LB, Luengo A, Danai LV, Bush LN, Diehl FF, Hosios AM, Lau AN, Elmiligy S, Malstrom S, Lewis CA, Vander Heiden MG (2018) Aspartate is an endogenous metabolic limitation for tumour growth. Nat Cell Biol 20:782–788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szablewski L (2013) Expression of glucose transporters in cancers. Biochem Biophys Acta 1835:164–169

    CAS  PubMed  Google Scholar 

  • Tan HW, Mo HY, Lau ATY, Xu YM (2018) Selenium species: current status and potentials in cancer prevention and therapy. Int J Mol Sci 20:1

    Article  Google Scholar 

  • Tang J, Yan T, Bao Y, Shen C, Yu C, Zhu X, Tian X, Guo F, Liang Q, Liu Q, Zhong M, Chen J, Ge Z, Li X, Chen X, Cui Y, Chen Y, Zou W, Chen H, Hong J, Fang JY (2019) LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc. Nat Commun 10:3499

    Article  PubMed  PubMed Central  Google Scholar 

  • Taparra K, Wang H, Malek R, Lafargue A, Barbhuiya MA, Wang X, Simons BW, Ballew M, Nugent K, Groves J, Williams RD, Shiraishi T, Verdone J, Yildirir G, Henry R, Zhang B, Wong J, Wang KK, Nelkin BD, Pienta KJ, Felsher D, Zachara NE, Tran PT (2018) O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J Clin Investig 128:4924–4937

    Article  PubMed  PubMed Central  Google Scholar 

  • Tateishi K, Iafrate AJ, Ho Q, Curry WT, Batchelor TT, Flaherty KT, Onozato ML, Lelic N, Sundaram S, Cahill DP, Chi AS, Wakimoto H (2016) Myc-driven glycolysis is a therapeutic target in glioblastoma. Clin Cancer Res 22:4452–4465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor S, Spugnini EP, Assaraf YG, Azzarito T, Rauch C, Fais S (2015) Microenvironment acidity as a major determinant of tumor chemoresistance: proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist Updates: Rev Comment Antimicrob Anticancer Chemother 23:69–78

    Article  Google Scholar 

  • Todenhofer T, Seiler R, Stewart C, Moskalev I, Gao J, Ladhar S, Kamjabi A, Al Nakouzi N, Hayashi T, Choi S, Wang Y, Frees S, Daugaard M, Oo HZ, Fisel P, Schwab M, Schaeffeler E, Douglas J, Hennenlotter J, Bedke J, Gibb EA, Fazli L, Stenzl A, Black PC (2018) Selective inhibition of the lactate transporter MCT4 reduces growth of invasive bladder cancer. Mol Cancer Ther 17:2746–2755

    Article  PubMed  Google Scholar 

  • Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AHC, Karra D, Piro RM, Felsberg J, Addington A, Lemke D, Weibrecht I, Hovestadt V, Rolli CG, Campos B, Turcan S, Sturm D, Witt H, Chan TA, Herold-Mende C, Kemkemer R, Konig R, Schmidt K, Hull WE, Pfister SM, Jugold M, Hutson SM, Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B (2013) BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19:901–908

    Article  PubMed  PubMed Central  Google Scholar 

  • Updegraff BL, Zhou X, Guo Y, Padanad MS, Chen PH, Yang C, Sudderth J, Rodriguez-Tirado C, Girard L, Minna JD, Mishra P, DeBerardinis RJ, O’Donnell KA (2018) Transmembrane protease TMPRSS11B promotes lung cancer growth by enhancing lactate export and glycolytic metabolism. Cell Rep 25:2223-2233 e2226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van den Heuvel AP, Jing J, Wooster RF, Bachman KE (2012) Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth. Cancer Biol Ther 13:1185–1194

    Article  PubMed  PubMed Central  Google Scholar 

  • Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329:1492–1499

    Article  CAS  PubMed  Google Scholar 

  • Vaupel P, Mayer A (2012) Availability, not respiratory capacity governs oxygen consumption of solid tumors. Int J Biochem Cell Biol 44:1477–1481

    Article  CAS  PubMed  Google Scholar 

  • Vincent EE, Sergushichev A, Griss T, Gingras MC, Samborska B, Ntimbane T, Coelho PP, Blagih J, Raissi TC, Choiniere L, Bridon G, Loginicheva E, Flynn BR, Thomas EC, Tavare JM, Avizonis D, Pause A, Elder DJ, Artyomov MN, Jones RG (2015) Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth. Mol Cell 60:195–207

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (2013) Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340:622–626

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu J, Jin X, Zhang D, Li D, Hao F, Feng Y, Gu S, Meng F, Tian M, Zheng Y, Xin L, Zhang X, Han X, Aravind L, Wei M (2017) O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect. Proc Natl Acad Sci USA 114:13732–13737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang F, He MM, Wang ZX, Li S, Jin Y, Ren C, Shi SM, Bi BT, Chen SZ, Lv ZD, Hu JJ, Wang ZQ, Wang FH, Wang DS, Li YH, Xu RH (2019a) Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer. BMC Cancer 19:460

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, Teo CC, Ang HY, Peh KLE, Yuan J, Ma S, Choo LSK, Basri N, Jiang X, Yu Q, Hillmer AM, Lim WT, Lim TKH, Takano A, Tan EH, Tan DSW, Ho YS, Lim B, Tam WL (2019b) Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25:825–837

    Article  CAS  PubMed  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watt MJ, Clark AK, Selth LA, Haynes VR, Lister N, Rebello R, Porter LH, Niranjan B, Whitby ST, Lo J, Huang C, Schittenhelm RB, Anderson KE, Furic L, Wijayaratne PR, Matzaris M, Montgomery MK, Papargiris M, Norden S, Febbraio M, Risbridger GP, Frydenberg M, Nomura DK, Taylor RA (2019) Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci Transl Med 11:1

    Article  Google Scholar 

  • Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC (2008) Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13:385–393

    Article  PubMed  PubMed Central  Google Scholar 

  • Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107:8788–8793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welsh JL, Wagner BA, van’t Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ II, Drisko J, Levine M, Buettner GR, Cullen JJ (2013) Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol 71:765–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Pavlides S, Tsirigos A, Ertel A, Pestell RG, Broda P, Minetti C, Lisanti MP, Sotgia F (2011) Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 10:4047–4064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wieman HL, Wofford JA, Rathmell JC (2007) Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 18:1437–1446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105:18782–18787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Witney TH, Carroll L, Alam IS, Chandrashekran A, Nguyen QD, Sala R, Harris R, DeBerardinis RJ, Agarwal R, Aboagye EO (2014) A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography. Can Res 74:1319–1328

    Article  CAS  Google Scholar 

  • Wojtkowiak JW, Rothberg JM, Kumar V, Schramm KJ, Haller E, Proemsey JB, Lloyd MC, Sloane BF, Gillies RJ (2012) Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Can Res 72:3938–3947

    Article  CAS  Google Scholar 

  • Xia J, Xu H, Zhang X, Allamargot C, Coleman KL, Nessler R, Frech I, Tricot G, Zhan F (2017) Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid. Ebio Med 18:41–49

    Google Scholar 

  • Xia Y, Ye B, Ding J, Yu Y, Alptekin A, Thangaraju M, Prasad PD, Ding ZC, Park EJ, Choi JH, Gao B, Fiehn O, Yan C, Dong Z, Zha Y, Ding HF (2019) Metabolic reprogramming by MYCN confers dependence on the serine-glycine-one-carbon biosynthetic pathway. Can Res 79:3837–3850

    Article  CAS  Google Scholar 

  • Xiao Y, Ma D, Yang YS, Yang F, Ding JH, Gong Y, Jiang L, Ge LP, Wu SY, Yu Q, Zhang Q, Bertucci F, Sun Q, Hu X, Li DQ, Shao ZM, Jiang YZ (2022) Comprehensive metabolomics expands precision medicine for triple-negative breast cancer. Cell Res 32:477–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P (2009) LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther 8:626–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z (2011) Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480:118–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK, Lu Z (2012) PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150:685–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu M (2011) Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci 89:65–71

    Article  CAS  PubMed  Google Scholar 

  • Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci USA 110:18226–18231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, Roper J, Chio EG II, Giannopoulou C, Rago A, Muley JM, Asara J, Paik O, Elemento Z, Chen DJ, Pappin LE, Dow N, Papadopoulos SSG, Cantley LC (2015) Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350:1391–1396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaytseva YY, Rychahou PG, Le AT, Scott TL, Flight RM, Kim JT, Harris J, Liu J, Wang C, Morris AJ, Sivakumaran TA, Fan T, Moseley H, Gao T, Lee EY, Weiss HL, Heuer TS, Kemble G, Evers M (2018) Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget 9:24787–24800

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, Djaballah H, Kanai M, Cheng EH, Judkins AR, Pawel B, Baggs J, Cherry S, Rabinowitz JD, Thompson CB (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56:205–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz JD, Ertl HCJ (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32:377-391 e379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao W, Prijic S, Urban BC, Tisza MJ, Zuo Y, Li L, Tan Z, Chen X, Mani SA, Chang JT (2016) Candidate antimetastasis drugs suppress the metastatic capacity of breast cancer cells by reducing membrane fluidity. Can Res 76:2037–2049

    Article  CAS  Google Scholar 

  • Zhong WD, Liang YX, Lin SX, Li L, He HC, Bi XC, Han ZD, Dai QS, Ye YK, Chen QB, Wang YS, Zeng GH, Zhu G, Zhang Z, Chen ZN, Wu CL (2012) Expression of CD147 is associated with prostate cancer progression. Int J Cancer 130:300–308

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Xu G, Wang Y, Xu Z, Liu X, Xu X, Ren G, Tian K (2017) Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells. Cell Cycle 16:73–81

    Article  CAS  PubMed  Google Scholar 

  • Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313:459–465

    Article  CAS  PubMed  Google Scholar 

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Funding

This research is co-financed by Greece and the European Union (European Social Fund-ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ)».

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Margetis, A.T. Metabolic targeting of malignant tumors: a need for systemic approach. J Cancer Res Clin Oncol 149, 2115–2138 (2023). https://doi.org/10.1007/s00432-022-04212-w

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