Metabolic Reprogramming and Molecular Rewiring in Cancer: Therapeutic Opportunities
Abstract
BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation.
CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression.
SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy.
KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring
Full Text:
PDFReferences
Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011; 27: 441-64, CrossRef.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008; 7: 11-20, CrossRef.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324: 1029-33, CrossRef.
Locasale JW, Cantley LC. Metabolic flux and the regulation of mammalian cell growth. Cell Metab. 2011; 14: 443-51, CrossRef.
Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011; 11: 85-95, CrossRef.
Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012; 21: 297-308, CrossRef.
Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012; 491: 364-73, CrossRef.
Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016; 30: 52-60, CrossRef.
Kaelin WG, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013; 153: 56-69, CrossRef.
Esteller M. Epigenetics in cancer. N Engl J Med. 2008; 358: 1148-59, CrossRef.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-74, CrossRef.
Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. 2012; 13: 270-6, CrossRef.
Kinnaird A, Michelakis ED. Metabolic modulation of cancer: a new frontier with great translational potential. J Mol Med. 2015; 93: 127-42, CrossRef.
Kinnaird A, Zhao S, Wellen KE, Michelakis ED. Metabolic control of epigenetics in cancer. Nat Rev Cancer. 2016; 16: 694-707, CrossRef.
Warburg O. On the origin of cancer cells. Science. 1956; 123: 309-14, CrossRef.
Weinhouse S. The Warburg hypothesis fifty years later. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1976; 87: 115-26, CrossRef.
Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006; 9: 425-34, CrossRef.
Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007; 274: 1393-418, CrossRef.
Izyumov DS, Avetisyan AV, Pletjushkina OY, Sakharov DV, Wirtz KW, Chernyak BV, et al. “Wages of fear”: transient threefold decrease in intracellular ATP level imposes apoptosis. Biochim Biophys Acta. 2004; 1658: 141-7, CrossRef.
Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell. 1999; 3: 159-67, CrossRef.
Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 2004; 101: 3329-35, CrossRef.
Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005; 120: 237-48, CrossRef.
Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015; 162: 1229-41, CrossRef.
Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015; 162: 1217-28, CrossRef.
Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013; 24: 213-28, CrossRef.
Dang CV. Links between metabolism and cancer. Genes Dev. 2012; 26: 877-90, CrossRef.
Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011; 11: 325-37, CrossRef.
Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010; 330: 1340-4, CrossRef.
Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015; 17: 351-9, CrossRef.
Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513: 559-63, CrossRef.
Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016; 41: 211-8, CrossRef.
Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009; 324: 1076-80, CrossRef.
Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci. 2010; 35: 505-13, CrossRef.
Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010; 40: 323-32, CrossRef.
Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013; 498: 109-12, CrossRef.
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004; 4: 579-91, CrossRef.
Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008; 8: 915-28, CrossRef.
Bock C, Lengauer T. Computational epigenetics. Bioinformatics. 2008; 24: 1-10, CrossRef.
Gillies RJ, Verduzco D, Gatenby RA. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer. 2012; 12: 487-93, CrossRef.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57-70, CrossRef.
Weinberg RA. Coming full circle-from endless complexity to simplicity and back again. Cell. 2014; 157: 267-71, CrossRef.
Yuneva MO, Fan TWM, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012; 15: 157-70, CrossRef.
Warburg O, Christian W, Griese A. Wasserstoffübertragendes co-ferment, seine zusammensetzung und wirkungsweise. Biochem Z. 1935; 282: 157-65.
Warburg O, Christian W. Isolierung u. Kristallisation des proteins des oxydierenden G{a ̈}rungsferments. Biochem Z. 1936; 286: 81-2.
Dickens F. Oxidation of phosphohexonate and pentose phosphoric acids by yeast enzymes. Biochem J. 1938; 32: 1626-44, CrossRef.
Ihmels J, Levy R, Barkai N. Principles of transcriptional control in the metabolic network of Saccharomyces cerevisiae. Nat Biotechnol. 2004; 22: 86-92, CrossRef.
Ralser M, Wamelink MM, Kowald A, Gerisch B, Heeren G, Struys EA, et al. Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J Biol. 2007; 6: 10, CrossRef.
Chechik G, Oh E, Rando O, Weissman J, Regev A, Koller D. Activity motifs reveal principles of timing in transcriptional control of the yeast metabolic network. Nat Biotechnol. 2008; 26: 1251-9, CrossRef.
Buescher JM, Moco S, Sauer U, Zamboni N. Ultrahigh performance liquid chromatography-tandem mass spectrometry method for fast and robust quantification of anionic and aromatic metabolites. Anal Chem. 2010; 82: 4403-12, CrossRef.
Fendt SM, Buescher JM, Rudroff F, Picotti P, Zamboni N, Sauer U. Tradeoff between enzyme and metabolite efficiency maintains metabolic homeostasis upon perturbations in enzyme capacity. Mol Syst Biol. 2010; 6: 356, CrossRef.
Grüning NM, Lehrach H, Ralser M. Regulatory crosstalk of the metabolic network. Trends in Biochemical Sciences. 2010; 35: 220-7, CrossRef.
Patil KR, Nielsen J. Uncovering transcriptional regulation of metabolism by using metabolic network topology. Proc Natl Acad Sci USA. 2005; 102: 2685-9, CrossRef.
Çakir T, Patil KR, Önsan ZI, Ülgen KÖ, Kirdar B, Nielsen J. Integration of metabolome data with metabolic networks reveals reporter reactions. Mol Syst Biol. 2006; 2: 50, CrossRef.
Ralser M, Wamelink MMC, Latkolik S, Jansen EEW, Lehrach H, Jakobs C. Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response. Nat Biotechnol. 2009; 27: 604-5, CrossRef.
Heinemann M, Sauer U. Systems biology of microbial metabolism. Curr Opin Microbiol. 2010; 13: 337-43, CrossRef.
Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010; 329: 1492-9, CrossRef.
Grüning NM, Ralser M. Sacrifice for survival. Nature. 2011; 480: 190-1, CrossRef.
Yamamoto T, Takano N, Ishiwata K, Ohmura M, Nagahata Y, Matsuura T, et al. Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Nat Commun. 2014; 5: 3480, CrossRef.
DeBerardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008; 18: 54-61, CrossRef.
Stincone A, Prigione A, Cramer T, Wamelink MMC, Campbell K, Cheung E, et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev. 2015; 90: 927-63, CrossRef.
Daran-Lapujade P, Jansen MLA, Daran J-M, van Gulik W, de Winde JH, Pronk JT. Role of transcriptional regulation in controlling fluxes in central carbon metabolism of Saccharomyces cerevisiae. A chemostat culture study. J Biol Chem. 2004; 279: 9125-38, CrossRef.
Buescher JM, Liebermeister W, Jules M, Uhr M, Muntel J, Botella E, et al. Global network reorganization during dynamic adaptations of Bacillus subtilis metabolism. Science. 2012; 335: 1099-103, CrossRef.
Kochanowski K, Sauer U, Chubukov V. Somewhat in control--the role of transcription in regulating microbial metabolic fluxes. Curr Opin Biotechnol. 2013; 24: 987-93, CrossRef.
Bensaad K, Tsuruta A, Selak MA, Vidal MNC, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006; 126: 107-20, CrossRef.
Rohwer N, Dame C, Haugstetter A, Wiedenmann B, Detjen K, Schmitt CA, et al. Hypoxia-inducible factor 1α determines gastric cancer chemosensitivity via modulation of p53 and NF-κB. PLOS ONE. 2010; 5: e12038, CrossRef.
Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T. Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol. 2011; 7: 501, CrossRef.
Tumanov S, Kamphorst JJ. Recent advances in expanding the coverage of the lipidome. Current Opinion in Biotechnology. 2017; 43: 127-33, CrossRef.
Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018; 18: 33-50, CrossRef.
Jennemann R, Gröne HJ. Cell-specific in vivo functions of glycosphingolipids: Lessons from genetic deletions of enzymes involved in glycosphingolipid synthesis. Prog Lipid Res. 2013; 52: 231-48, CrossRef.
Hishikawa D, Hashidate T, Shimizu T, Shindou H. Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells. J Lipid Res. 2014; 55: 799-807, CrossRef.
Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010; 327: 46-50, CrossRef.
Capper CP, Rae JM, Auchus RJ. The Metabolism, analysis, and targeting of steroid hormones in breast and prostate cancer. Horm Canc. 2016; 7: 149-64, CrossRef.
Wang D, DuBois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010; 10: 181-93, CrossRef.
Fabian CJ, Kimler BF, Hursting SD. Omega-3 fatty acids for breast cancer prevention and survivorship. Breast Cancer Res. 2015; 17: 62, CrossRef.
Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell metabolism. 2020; 31: 62-76, CrossRef.
Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015; 11: 9-15, CrossRef.
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood. 2007; 109: 3812-9, CrossRef.
Gomaraschi M. Role of lipoproteins in the microenvironment of hormone-dependent cancers. Trends Endrocrinol Metab. 2020; 31: 256-68, CrossRef.
Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016; 16: 732-49, CrossRef.
Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005; 24: 6314-22, CrossRef.
Berwick DC, Hers I, Heesom KJ, Moule SK, Tavareá JM. The Identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem. 2002; 277: 33895-900, CrossRef.
Shackelford DB, Shaw RJ. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9: 563-75, CrossRef.
Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res. 2003; 44: 655-67, CrossRef.
Schroepfer GJ. Oxysterols: Modulators of cholesterol metabolism and other processes. Physiol Rev. 2000; 80: 361-554, CrossRef.
Krycer JR, Brown AJ. Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective. Biochim Biophys Acta Rev Cancer. 2013; 1835: 219-29, CrossRef.
Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 2016; 16: 718-31, CrossRef.
Lee J, Jung KH, Park YS, Ahn JB, Shin SJ, Im SA, et al. Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal patients: a multicenter phase II study. Cancer Chemother Pharmacol. 2009; 64: 657-63, CrossRef.
Liu JC, Hao WR, Hsu YP, Sung LC, Kao PF, Lin CF, et al. Statins dose-dependently exert a significant chemopreventive effect on colon cancer in patients with chronic obstructive pulmonary disease: A population-based cohort study. Oncotarget. 2016; 7: 65270-83, CrossRef.
Sehdev A, Shih Y, Huo D, Vekhter B, Lyttle C, Polite B. The role of statins for primary prevention in non-elderly colorectal cancer patients. Nat Rev Mol Cell Biol. 2017; 18: 361-74. Anticancer Res. 2014; 34: 5043-50, PMID.
Gray RT, Loughrey MB, Bankhead P, Cardwell CR, McQuaid S, O’Neill RF, et al. Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study. Br J Cancer. 2017; 116: 1652-9, CrossRef.
Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, et al. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015; 113: 1421-6, CrossRef.
Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun. 2018; 38: 27, CrossRef.
Jones SF, Infante JR. Molecular pathways: fatty acid synthase. Clin Cancer Res. 2015; 21: 5434-8, CrossRef.
Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med. 2016; 22: 1108-19, CrossRef.
Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 2014; 20: 280-94, CrossRef.
Zhang N, Zhang H, Liu Y, Su P, Zhang J, Wang X, et al. SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2. Cell Death Differ. 2019; 26: 843-59, CrossRef.
Ma YQ, Liu ZH. Excellent adsorption performance for Congo red on hierarchical porous magnesium borate microsphere prepared by a template-free hydrothermal method. J Taiwan Inst Chem Eng. 2018; 86: 92-100, CrossRef.
Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med. 2016; 22: 427-32, CrossRef.
Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-Oncology. 2017; 19: 43-54, CrossRef.
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010; 140: 49-61, CrossRef.
Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014; 19: 393-406, CrossRef.
Lawrence MS, Stojanov P, Mermel CH, Garraway LA, Golub TR, Meyerson M, et al. Discovery and saturation analysis of cancer genes across 21 tumor types. Nature. 2014; 505: 495-501, CrossRef.
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017; 170: 605-35, CrossRef.
Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017; 169: 381-405, CrossRef.
Greer EL, Brunet A. FOXO transcription factors in ageing and cancer: FOXO factors in ageing and cancer. Acta Physiol. 2007; 192: 19-28, CrossRef.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96: 857-68, CrossRef.
Hornsveld M, Dansen TB, Derksen PW, Burgering BMT. Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol. 2018; 50: 90-100, CrossRef.
Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol. 2003; 23: 7315-28, CrossRef.
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004; 64: 3892-9, CrossRef.
Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem. 2001; 276: 12041-8, CrossRef.
Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001; 15: 1406-18, CrossRef.
Edinger AL, Thompson CB. Antigen-presenting cells control T cell proliferation by regulating amino acid availability. Proc Natl Acad Sci USA. 2002; 99: 1107-9, CrossRef.
Buzzai M, Bauer DE, Jones RG, Deberardinis RJ, Hatzivassiliou G, Elstrom RL, et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene. 2005; 24: 4165-73, CrossRef.
DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016; 2: e1600200, CrossRef.
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010; 107: 8788-93, CrossRef.
Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, et al. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol. 2014; 24: 2274-80, CrossRef.
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020; 20: 74-88, CrossRef.
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007; 7: 763-77, CrossRef.
Ben-Sahra I, Howell JJ, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science. 2013; 339: 1323-8, CrossRef.
Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers (Basel). 2019; 11: 688, CrossRef.
Tong X, Zhao F, Thompson CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009; 19: 32-7, CrossRef.
Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science. 2013; 339: 1320-3, CrossRef.
Valvezan AJ, Turner M, Belaid A, Lam HC, Miller SK, McNamara MC, et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell. 2017; 32: 624-638.e5, CrossRef.
Huang F, Ni M, Chalishazar MD, Huffman KE, Kim J, Cai L, et al. Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Cell Metab. 2018; 28: 369-382.e5, CrossRef.
Hoxhaj G, Hughes-Hallett J, Timson RC, Ilagan E, Yuan M, Asara JM, et al. The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Rep. 2017; 21: 1331-46, CrossRef.
Emmanuel N, Ragunathan S, Shan Q, Wang F, Giannakou A, Huser N, et al. Purine nucleotide availability regulates mTORC1 activity through the Rheb GTPase. Cell Rep. 2017; 19: 2665-80, CrossRef.
Hoxhaj G, Manning BD. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020; 20: 74-88, CrossRef.
Salmeen A, Andersen JN, Myers MP, Meng T-C, Hinks JA, Tonks NK, et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature. 2003; 423: 769-73, CrossRef.
Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002; 277: 20336–42, CrossRef.
Raman D, Pervaiz S. Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression. Redox Biol. 2019; 27: 101105, CrossRef.
Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018; 15: 273-91, CrossRef.
Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018; 560: 499-503, CrossRef.
Ilagan E, Manning BD. Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer. 2016; 2: 241-51, CrossRef.
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019; 380: 1929-40, CrossRef.
Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell. 2015; 162: 552-63, CrossRef.
Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013; 13: 572-83, CrossRef.
Farber S, Cutler EC, Hawkins JW, Harrison JH, Peirce EC, Lenz GG. The action of pteroylglutamic conjugates on man. Science. 1947; 106: 619-21, CrossRef.
Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948; 238: 787-93, CrossRef.
Chabner BA, Roberts TG. Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer. 2005; 5: 65-72, CrossRef.
Johnston PG, Takimoto CH, Grem JL, Fidias P, Grossbard ML, Chabner BA, et al. Antimetabolites. Cancer Chemother Biol Response Modif. 1997; 17: 1-39, PMID.
Davis JL, Fallon HJ, Morris HP. Two enzymes of serine metabolism in rat liver and hepatomas. Cancer Res. 1970; 30: 2917-20, PMID.
Snell K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Adv Enzym Regul. 1984; 22: 325-400, CrossRef.
Israelsen WJ, Vander Heiden MG. Pyruvate kinase: function, regulation and role in cancer. Semin Cell Dev Biol. 2015; 43: 43-51, CrossRef.
Ibsen KH, Marles SW. Inhibition of chicken pyruvate kinases by amino acids. Biochemistry. 1976; 15: 1073-9, CrossRef.
Eigenbrodt E, Leib S, Krămer W, Friis R, Schoner W. Structural and kinetic differences between the M2 type pyruvate kinases from lung and various tumors. Biomed Biochim Acta. 1983; 42: S278-82, PMID.
Chaneton B, Hillmann P, Zheng L, Martin ACL, Maddocks ODK, Chokkathukalam A, et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature. 2012; 491: 458-62, CrossRef.
Anastasiou D, Yu Y, Israelsen WJ, Jiang J-K, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012; 8: 839-47, CrossRef.
Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E, et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol. 2012; 19: 1187-98, CrossRef.
Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J, et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 2014; 4: 1406-17, CrossRef.
Maddocks ODK, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2013; 493: 542-6, CrossRef.
Labuschagne CF, van den Broek NJF, Mackay GM, Vousden KH, Maddocks ODK. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 2014; 7: 1248-58, CrossRef.
Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011; 476: 346-50, CrossRef.
Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, et al. Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth. Oncotarget. 2013; 4: 2502-11, CrossRef.
DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015; 47: 1475-81, CrossRef.
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012; 336: 1040-4, CrossRef.
Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 2012; 148: 259-72, CrossRef.
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009; 457: 910-4, CrossRef.
Farber S. Some observations on the effect of folic acid antagonists on acute leukemia and other forms of incurable cancer. Blood. 1949; 4: 160-7, CrossRef.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003; 21: 2636-44, CrossRef.
Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011; 10: 671-84, CrossRef.
Cheson BD. New antimetabolites in the treatment of human malignancies. Semin Oncol. 1992; 19: 695-706, PMID.
Bertino JR. Folate antagonists. In: Fox BW, Fox M, editors. Antitumor Drug Resistance. Berlin, Heidelberg: Springer Berlin Heidelberg; 1984. p. 615-31, CrossRef.
Sirotnak FM, editor. Folate Antagonists as Therapeutic Agents. New York: Academic Press; 1984, NLMID.
Baram J, Allegra CJ, Fine RL, Chabner BA. Effect of methotrexate on intracellular folate pools in purified myeloid precursor cells from normal human bone marrow. J Clin Invest. 1987; 79: 692-7, CrossRef.
Allegra CJ, Fine RL, Drake JC, Chabner BA. The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis. J Biol Chem. 1986; 261: 6478-85, CrossRef.
Li X, Wilmanns M, Thornton J, Köhn M. Elucidating human phosphatase-substrate networks. Sci Signal. 2013; 6: rs10, CrossRef.
Sacco F, Perfetto L, Castagnoli L, Cesareni G. The human phosphatase interactome: An intricate family portrait. FEBS Lett. 2012; 586: 2732-9, CrossRef.
Gil RS, Vagnarelli P. Protein phosphatases in chromatin structure and function. Biochim Biophys Acta Mol Cell Res. 2019; 1866: 90-101, CrossRef.
Alberts B, editor. Molecular Biology of The Cell. 4th ed. New York: Garland Science; 2002, NLMID.
Kathryn L. McCance, Sue E. Huether. Pathophysiology. The Biologic Basis for Disease in Adults and Children. 7th Edition. St. Louis: Elsevier Health Sciences; 2014, NLMID.
Heinrich R, Neel BG, Rapoport TA. Mathematical models of protein kinase signal transduction. Mol Cell. 2002; 9: 957-70, CrossRef.
Roskoski R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012; 66: 105-43, CrossRef.
Miller ML, Jensen LJ, Diella F, Jørgensen C, Tinti M, Li L, et al. Linear motif atlas for phosphorylation-dependent signaling. Sci Signal. 2008; 1: ra2, CrossRef.
Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009; 21: 140-6, CrossRef.
Capra M, Nuciforo PG, Confalonieri S, Quarto M, Bianchi M, Nebuloni M, et al. Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res. 2006; 66: 8147-54, CrossRef.
Barford D. Molecular mechanisms of the protein serine/threonine phosphatases. Trends Biochem Sci. 1996; 21: 407-12, CrossRef.
Zhang ZY. Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annu Rev Pharmacol Toxicol. 2002; 42: 209-34, CrossRef.
Stern DF. Phosphoproteomics for oncology discovery and treatment. Expert Opin Ther Targets. 2005; 9: 851-60, CrossRef.
Jin J, Pawson T. Modular evolution of phosphorylation-based signalling systems. Philos Trans R Soc Lond B Biol Sci. 2012; 367: 2540-55, CrossRef.
Liu Y, Chance MR. Integrating phosphoproteomics in systems biology. Comput Struct Biotechnol J. 2014; 10: 90-7, CrossRef.
Harsha HC, Pandey A. Phosphoproteomics in cancer. Mol Oncol. 2010; 4: 482-95, CrossRef.
Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009; 21: 177-84, CrossRef.
Sharma A, Tan TH, Cheetham G, Scott HS, Brown MP. Rare and novel epidermal growth factor receptor mutations in non-small-cell lung cancer and lack of clinical response to gefitinib in two cases. J Thorac Oncol. 2012; 7: 941-2, CrossRef.
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004; 10: 789-99, CrossRef.
Petricoin EF, Zoon KC, Kohn EC, Barrett JC, Liotta LA. Clinical proteomics: translating benchside promise into bedside reality. Nat Rev Drug Discov. 2002; 1: 683-95, CrossRef.
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3: 415-28, CrossRef.
Tarrant MK, Cole PA. The chemical biology of protein phosphorylation. Annu Rev Biochem. 2009; 78: 797-825, CrossRef.
Paul M, Mukhopadhyay A. Tyrosine kinase – role and significance in cancer. Int J Med Sci. 2004; 1: 101-15, CrossRef.
Sawyers CL. Shifting paradigms: the seeds of oncogene addiction. Nat Med. 2009; 15: 1158-61, CrossRef.
Hainaut P, Plymoth A. Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy. Curr Opin Oncol. 2013; 25: 50-1, CrossRef.
Gonzalez de Castro D, Clarke PA, Al-Lazikani B, Workman P. Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. Clin Pharmacol Ther. 2013; 93: 252-9, CrossRef.
Druker BJ. Imatinib mesylate in the treatment of chronic myeloid leukaemia. Expert Opin Pharmacother. 2003; 4: 963-71, CrossRef.
Stegmeier F, Warmuth M, Sellers WR, Dorsch M. Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clin Pharmacol Ther. 2010; 87: 543-52, CrossRef.
Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther. 2004; 3: 772-5, CrossRef.
Serra V, Markman B, Scaltriti M, Eichhorn PJA, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68: 8022-30, CrossRef.
Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002; 62: 6997-7000, PMID.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364: 2507-16, CrossRef.
Young K, Minchom A, Larkin J. BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future Oncol. 2012; 8: 499-507, CrossRef.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361: 947-57, CrossRef.
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304: 1497-500, CrossRef.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008; 372: 449-56, CrossRef.
Abdurahman A, Anwar J, Turghun A, Niyaz M, Zhang L, Awut I. Epidermal growth factor receptor gene mutation status and its association with clinical characteristics and tumor markers in non-small-cell lung cancer patients in Northwest China. Mol Clin Oncol. 2015; 3: 847-50, CrossRef.
Ulivi P, Chiadini E, Dazzi C, Dubini A, Costantini M, Medri L, et al. Nonsquamous, non-small-cell lung cancer patients who carry a double mutation of EGFR, EML4-ALK or KRAS: frequency, clinical-pathological characteristics, and response to therapy. Clinical Lung Cancer. 2016; 17: 384-90, CrossRef.
Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371: 1867-76, CrossRef.
Carvajal-Hausdorf DE, Schalper KA, Pusztai L, Psyrri A, Kalogeras KT, Kotoula V, et al. Measurement of domain-specific HER2 (ERBB2) expression may classify benefit from trastuzumab in breast cancer. J Natl Cancer Inst. 2015; 107: djv136, CrossRef.
Hasskarl J. Sorafenib: targeting multiple tyrosine kinases in cancer. Recent Results Cancer Res. 2014; 201: 145-64, CrossRef.
Aita Y, Ishii K, Saito Y, Ikeda T, Kawakami Y, Shimano H, et al. Sunitinib inhibits catecholamine synthesis and secretion in pheochromocytoma tumor cells by blocking VEGF receptor 2 via PLC-γ-related pathways. Am J Physiol Endocrinol Metab. 2012; 303: E1006-14, CrossRef.
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006; 368: 1329-38, CrossRef.
Czarnecka AM, Solarek W, Kornakiewicz A, Szczylik C. Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer. Oncology Reports. 2016; 35: 1433-42, CrossRef.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002; 20: 719-26, CrossRef.
Murray BW, Miller N. Durability of kinase-directed therapies--a network perspective on response and resistance. Mol Cancer Ther. 2015; 14: 1975-84, CrossRef.
Cutillas PR. Role of phosphoproteomics in the development of personalized cancer therapies. Proteomics Clin Appl. 2015; 9: 383-95, CrossRef.
Ardito F, Giuliani M, Perrone D, Troiano G, Muzio LL. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J Mol Med. 2017; 40: 271-80, CrossRef.
Vasan K, Werner M, Chandel NS. Mitochondrial metabolism as a target for cancer therapy. Cell Metab. 2020; 32: 341-52, CrossRef.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016; 23: 27-47, CrossRef.
Vander Heiden MG, DeBerardinis RJ. Understanding the Intersections between metabolism and cancer biology. Cell. 2017; 168: 657-69, CrossRef.
Olson KA, Schell JC, Rutter J. Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies. Trends Biochem Sci. 2016; 41: 219-30, CrossRef.
Samanta D, Semenza GL. Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. Biochim Biophys Acta Rev Cancer. 2018; 1870: 15-22, CrossRef.
Xie H, Simon MC. Oxygen availability and metabolic reprogramming in cancer. J Biol Chem. 2017; 292: 16825-32, CrossRef.
DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020; 2: 127-9, CrossRef.
Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016; 61: 667-76, CrossRef.
Bensard CL, Wisidagama DR, Olson KA, Berg JA, Krah NM, Schell JC, et al. Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell Metab. 2020; 31: 284-300.e7, CrossRef.
Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020; 31: 267-283.e12, CrossRef.
Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020; 368: eaaw5473, CrossRef.
Jain RK, Munn LL, Fukumura D. Dissecting tumour pathophysiology using intravital microscopy. Nat Rev Cancer. 2002; 2: 266-76. https://doi.org/10.1038/nrc778">CrossRef.
Le A, Stine ZE, Nguyen C, Afzal J, Sun P, Hamaker M, et al. Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia–cell cycle dual reporter. PNAS. 2014; 111: 12486-91, CrossRef.
Rumsey WL, Schlosser C, Nuutinen EM, Robiolio M, Wilson DF. Cellular energetics and the oxygen dependence of respiration in cardiac myocytes isolated from adult rat. J Biol Chem. 1990; 265: 15392-402, CrossRef.
Pollak M. Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat Med. 2014; 20: 591-3, CrossRef.
Dowling RJO, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012; 48: R31-43, CrossRef.
Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 2011; 30: 1174-82, CrossRef.
Hirschey MD, Zhao Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol Cell Proteom. 2015; 14: 2308-15, CrossRef.
Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res. 2010; 3: 1066-76, CrossRef.
Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci. 2008; 99: 2136-41, CrossRef.
Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015; 107: djv006, CrossRef.
Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell. 2015; 162: 540-51, CrossRef.
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012; 12: 159-69, CrossRef.
Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, et al. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab. 2019; 29: 399-416.e10, CrossRef.
Chen JJ, Jones ME. The cellular location of dihydroorotate dehydrogenase: Relation to de novo biosynthesis of pyrimidines. Arch Biochem Biophys. 1976; 176: 82-90, CrossRef.
Rawls J, Knecht W, Diekert K, Lill R, Löffler M. Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase. Eur J Biochem. 2000; 267: 2079-87, CrossRef.
Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, Werner M, et al. Mitochondrial ubiquinol oxidation is necessary for tumour growth. Nature. 2020; 585: 288-92, CrossRef.
Brown KK, Spinelli JB, Asara JM, Toker A. Adaptive reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. Cancer Discov. 2017; 7: 391-9, CrossRef.
Koundinya M, Sudhalter J, Courjaud A, Lionne B, Touyer G, Bonnet L, et al. Dependence on the pyrimidine biosynthetic enzyme DHODH is a synthetic lethal vulnerability in mutant KRAS-driven cancers. Cell Chem Biol. 2018; 25: 705-717.e11, CrossRef.
Li L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, et al. Identification of DHODH as a therapeutic target in small cell lung cancer. Sci Transl Med. 2019; 11: eaaw7852, CrossRef.
Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, et al. PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition. Cancer Discov. 2017; 7: 380-90, CrossRef.
Sykes DB. The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia. Expert Opin Ther Targets. 2018; 22: 893-8, CrossRef.
Wang X, Yang K, Wu Q, Kim LJY, Morton AR, Gimple RC, et al. Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells. Sci Transl Med. 2019; 11: eaau4972, CrossRef.
White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 2011; 471: 518-22, CrossRef.
Stuart SD, Schauble A, Gupta S, Kennedy AD, Keppler BR, Bingham PM, et al. A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014; 2: 4, CrossRef.
Alistar AT, Desnoyers R, D’Agostino RJ, Pasche B. CPI-613 enhances FOLFIRINOX response rate in stage IV pancreatic cancer. Ann Oncol. 2016; 27: vi228, CrossRef.
Pardee TS, Lee K, Luddy J, Maturo C, Rodriguez R, Isom S, et al. A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clin Cancer Res. 2014; 20: 5255-64, CrossRef.
Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016; 16: 619-34, CrossRef.
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15: 110-21, CrossRef.
Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, et al. Keap1 loss promotes Kras -driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017; 23: 1362-8, CrossRef.
Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ, et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. PNAS. 2015; 112: 6539-44, CrossRef.
Xiang Y, Stine ZE, Xia J, Lu Y, O’Connor RS, Altman BJ, et al. Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest. 2015; 125: 2293-306, CrossRef.
Courtney KD, Bezwada D, Mashimo T, Pichumani K, Vemireddy V, Funk AM, et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 2018; 28:793-800.e2, CrossRef.
Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, et al. Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci Transl Med. 2018; 10: eaat5933, CrossRef.
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35: 871-82, CrossRef.
Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014; 40: 692-705, CrossRef.
Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019; 366: 1013-21, CrossRef.
Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012; 150: 12-27, CrossRef.
Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011; 17: 330-9, CrossRef.
Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014; 54: 716-27, CrossRef.
Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992; 69: 915-26, CrossRef.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324: 930-5, CrossRef.
Lu Y, Wajapeyee N, Turker MS, Glazer PM. Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1. Cell Rep. 2014; 8: 501-13, CrossRef.
Chen W, Guéron M. The inhibition of bovine heart hexokinase by 2-deoxy-d-glucose-6-phosphate: characterization by 31P NMR and metabolic implications. Biochimie. 1992; 74: 867-73, CrossRef.
Miranda-Gonçalves V, Lameirinhas A, Henrique R, Jerónimo C. Metabolism and epigenetic interplay in cancer: regulation and putative therapeutic targets. Front Genet. 2018; 9: 427, CrossRef.
Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012; 13: 97-109, CrossRef.
Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017; 357: eaal2380, CrossRef.
Wong CC, Qian Y, Yu J. Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches. Oncogene. 2017; 36: 3359-74, CrossRef.
Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017; 7: 478-93, CrossRef.
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013; 340: 622-6, CrossRef.
Katada S, Imhof A, Sassone-Corsi P. Connecting threads: epigenetics and metabolism. Cell. 2012; 148: 24-8, CrossRef.
Nowicki S, Gottlieb E. Oncometabolites: tailoring our genes. FEBS J. 2015; 282: 2796-805, CrossRef.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009; 360: 765-73, CrossRef.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17: 225-34, CrossRef.
The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487: 330-7, CrossRef.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009; 462: 739-44, CrossRef.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19: 17-30, CrossRef.
Shim EH, Livi CB, Rakheja D, Tan J, Benson D, Parekh V, et al. l-2-hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 2014; 4: 1290-8, CrossRef.
Liu XS, Little JB, Yuan Z-M. Glycolytic metabolism influences global chromatin structure. Oncotarget. 2015; 6: 4214-25, CrossRef.
Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 2015; 21: 392-402, CrossRef.
Simpson NE, Tryndyak VP, Beland FA, Pogribny IP. An in vitro investigation of metabolically sensitive biomarkers in breast cancer progression. Breast Cancer Res Treat. 2012; 133: 959-68, CrossRef.
Robinson MM, Mcbryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, et al. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J. 2007; 406: 407-14, CrossRef.
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18: 207-19, CrossRef.
Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013; 340: 626-30, CrossRef.
Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS ONE. 2015; 10: e0133813, CrossRef.
Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister SM, et al. Glioma. Nat Rev Dis Primers. 2015; 1: 15017, CrossRef.
Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005; 353: 811-22, CrossRef.
Cloughesy TF, Cavenee WK, Mischel PS. Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol. 2014; 9: 1-25, CrossRef.
Bi J, Chowdhry S, Wu S, Zhang W, Masui K, Mischel PS. Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets. Nat Rev Cancer. 2020; 20: 57-70, CrossRef.
Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011; 14: 724-38, CrossRef.
Venneti S, Thompson CB. Metabolic reprogramming in brain tumors. Annu Rev Pathol. 2017; 12: 515-45, CrossRef.
Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013; 155: 462-77, CrossRef.
Parsons DW, Jones S, Zhang X, Lin JCH, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321: 1807-12, CrossRef.
Marin-Valencia I, Yang C, Mashimo T, Cho S, Baek H, Yang XL, et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 2012; 15: 827-37, CrossRef.
Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 2015; 21: 805-21, CrossRef.
Duman C, Yaqubi K, Hoffmann A, Acikgöz AA, Korshunov A, Bendszus M, et al. Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metab. 2019; 30: 274-289.e5, CrossRef.
Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal. 2009; 2: ra82, CrossRef.
Gimple RC, Kidwell RL, Kim LJY, Sun T, Gromovsky AD, Wu Q, et al. Glioma stem cell-specific superenhancer promotes polyunsaturated fatty-acid synthesis to support EGFR signaling. Cancer Discov. 2019; 9: 1248-67, CrossRef.
The Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015; 372: 2481-98, CrossRef.
Riemenschneider MJ, Büschges R, Wolter M, Reifenberger J, Boström J, Kraus JA, et al. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 1999; 59: 6091-6, PMID.
deCarvalho AC, Kim H, Poisson LM, Winn ME, Mueller C, Cherba D, et al. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet. 2018; 50: 708-17, CrossRef.
Verhaak RGW, Bafna V, Mischel PS. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat Rev Cancer. 2019; 19: 283-8, CrossRef.
Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med. 2013: a014217, CrossRef.
Kim J, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 2007; 27: 7381-93, CrossRef.
Kim J, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol. 2004; 24: 5923-36, CrossRef.
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275: 21797-800, CrossRef.
Tateishi K, Iafrate AJ, Ho Q, Curry WT, Batchelor TT, Flaherty KT, et al. Myc-driven glycolysis is a therapeutic target in glioblastoma. Clin Cancer Res. 2016; 22: 4452-65, CrossRef.
Turner KM, Deshpande V, Beyter D, Koga T, Rusert J, Lee C, et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature. 2017; 543: 122-5, CrossRef.
Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014; 20: 306-19, CrossRef.
Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, et al. Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer. 2010; 126: 2282-95, CrossRef.
Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, et al. Acetate dependence of tumors. Cell. 2014; 159: 1591-602, CrossRef.
Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol Cell. 2017; 66: 684-697.e9, CrossRef.
Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab. 2013; 17: 1000-8, CrossRef.
Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y, Raviram R, et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature. 2019; 569: 570–5, CrossRef.
DOI: https://doi.org/10.18585/inabj.v13i2.1598
Copyright (c) 2021 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute
