ENTRY ko05230 Pathway NAME Central carbon metabolism in cancer DESCRIPTION Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53. CLASS Human Diseases; Cancer: overview PATHWAY_MAP ko05230 Central carbon metabolism in cancer ORTHOLOGY K00016 LDH; L-lactate dehydrogenase [EC:1.1.1.27] K00031 IDH1, IDH2, icd, IDP; isocitrate dehydrogenase [EC:1.1.1.42] K00036 G6PD, zwf; glucose-6-phosphate 1-dehydrogenase [EC:1.1.1.49 1.1.1.363] K00161 PDHA; pyruvate dehydrogenase E1 component subunit alpha [EC:1.2.4.1] K00162 PDHB; pyruvate dehydrogenase E1 component subunit beta [EC:1.2.4.1] K00844 HK; hexokinase [EC:2.7.1.1] K00850 pfkA, PFK; 6-phosphofructokinase 1 [EC:2.7.1.11] K00873 PK, pyk; pyruvate kinase [EC:2.7.1.40] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K01110 PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67] K01425 glsA, GLS; glutaminase [EC:3.5.1.2] K01834 PGAM, gpmA; 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase [EC:5.4.2.11] K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K02833 HRAS; GTPase HRas K03176 NTRK1, TRKA; neurotrophic tyrosine kinase receptor type 1 [EC:2.7.10.1] K04361 EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1] K04362 FGFR1, CD331; fibroblast growth factor receptor 1 [EC:2.7.10.1] K04363 PDGFRA, CD140A; platelet-derived growth factor receptor alpha [EC:2.7.10.1] K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2] K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2] K04371 ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24] K04377 MYC; Myc proto-oncogene protein K04451 TP53, P53; tumor protein p53 K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K05083 ERBB2, HER2, CD340; receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1] K05089 PDGFRB, CD140B; platelet-derived growth factor receptor beta [EC:2.7.10.1] K05091 KIT, SCFR, CD117; proto-oncogene tyrosine-protein kinase Kit [EC:2.7.10.1] K05092 FLT3, FLK2, CD135; fms-related tyrosine kinase 3 [EC:2.7.10.1] K05093 FGFR2, CD332; fibroblast growth factor receptor 2 [EC:2.7.10.1] K05094 FGFR3, CD333; fibroblast growth factor receptor 3 [EC:2.7.10.1] K05099 MET, HGFR; proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1] K05101 NTRK3, TRKC; neurotrophic tyrosine kinase, receptor type 3 [EC:2.7.10.1] K05126 RET; proto-oncogene tyrosine-protein kinase Ret [EC:2.7.10.1] K05616 SLC1A5; solute carrier family 1 (neutral amino acid transporter), member 5 K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07299 SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 K07593 SLC2A2, GLUT2; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2 K07827 KRAS, KRAS2; GTPase KRas K07828 NRAS; GTPase NRas K08180 SLC16A3; MFS transporter, MCT family, solute carrier family 16 (monocarboxylic acid transporters), member 3 K08268 HIF1A; hypoxia-inducible factor 1 alpha K11413 SIRT3, SIR2L3; NAD-dependent protein deacetylase sirtuin 3 [EC:2.3.1.286] K11416 SIRT6, SIR2L6; NAD-dependent protein deacetylase sirtuin 6 [EC:2.3.1.286] K12077 PDK1; pyruvate dehydrogenase kinase isoform 1 [EC:2.7.11.2] K12407 GCK; glucokinase [EC:2.7.1.2] K13780 SLC7A5, LAT1; solute carrier family 7 (L-type amino acid transporter), member 5 K14634 TIGAR; fructose-2,6-bisphosphatase [EC:3.1.3.46] K23755 SCO2; protein SCO2 COMPOUND C00022 Pyruvate C00024 Acetyl-CoA C00025 L-Glutamate C00026 2-Oxoglutarate C00031 D-Glucose C00036 Oxaloacetate C00037 Glycine C00041 L-Alanine C00042 Succinate C00049 L-Aspartate C00062 L-Arginine C00064 L-Glutamine C00065 L-Serine C00073 L-Methionine C00074 Phosphoenolpyruvate C00078 L-Tryptophan C00079 L-Phenylalanine C00082 L-Tyrosine C00085 D-Fructose 6-phosphate C00092 D-Glucose 6-phosphate C00097 L-Cysteine C00122 Fumarate C00123 L-Leucine C00135 L-Histidine C00148 L-Proline C00149 (S)-Malate C00152 L-Asparagine C00158 Citrate C00183 L-Valine C00186 (S)-Lactate C00197 3-Phospho-D-glycerate C00311 Isocitrate C00354 D-Fructose 1,6-bisphosphate C00407 L-Isoleucine C00631 2-Phospho-D-glycerate C00665 beta-D-Fructose 2,6-bisphosphate C00704 Superoxide REFERENCE PMID:23279446 AUTHORS Soga T TITLE Cancer metabolism: key players in metabolic reprogramming. JOURNAL Cancer Sci 104:275-81 (2013) DOI:10.1111/cas.12085 REFERENCE PMID:19460998 AUTHORS Vander Heiden MG, Cantley LC, Thompson CB TITLE Understanding the Warburg effect: the metabolic requirements of cell proliferation. JOURNAL Science 324:1029-33 (2009) DOI:10.1126/science.1160809 REFERENCE PMID:23071355 AUTHORS Teicher BA, Linehan WM, Helman LJ TITLE Targeting cancer metabolism. JOURNAL Clin Cancer Res 18:5537-45 (2012) DOI:10.1158/1078-0432.CCR-12-2587 REFERENCE PMID:21127244 AUTHORS Levine AJ, Puzio-Kuter AM TITLE The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. JOURNAL Science 330:1340-4 (2010) DOI:10.1126/science.1193494 REFERENCE PMID:24079832 AUTHORS Amoedo ND, Valencia JP, Rodrigues MF, Galina A, Rumjanek FD TITLE How does the metabolism of tumour cells differ from that of normal cells. JOURNAL Biosci Rep 33:e00080 (2013) DOI:10.1042/BSR20130066 REFERENCE PMID:21258394 AUTHORS Cairns RA, Harris IS, Mak TW TITLE Regulation of cancer cell metabolism. JOURNAL Nat Rev Cancer 11:85-95 (2011) DOI:10.1038/nrc2981 REFERENCE PMID:22237205 AUTHORS Munoz-Pinedo C, El Mjiyad N, Ricci JE TITLE Cancer metabolism: current perspectives and future directions. JOURNAL Cell Death Dis 3:e248 (2012) DOI:10.1038/cddis.2011.123 REFERENCE PMID:22156302 AUTHORS Cairns RA, Harris I, McCracken S, Mak TW TITLE Cancer cell metabolism. JOURNAL Cold Spring Harb Symp Quant Biol 76:299-311 (2011) DOI:10.1101/sqb.2011.76.012856 REFERENCE PMID:18538731 AUTHORS Kroemer G, Pouyssegur J TITLE Tumor cell metabolism: cancer's Achilles' heel. JOURNAL Cancer Cell 13:472-82 (2008) DOI:10.1016/j.ccr.2008.05.005 REFERENCE PMID:18177721 AUTHORS DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB TITLE The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. JOURNAL Cell Metab 7:11-20 (2008) DOI:10.1016/j.cmet.2007.10.002 REFERENCE PMID:21508971 AUTHORS Koppenol WH, Bounds PL, Dang CV TITLE Otto Warburg's contributions to current concepts of cancer metabolism. JOURNAL Nat Rev Cancer 11:325-37 (2011) DOI:10.1038/nrc3038 REFERENCE PMID:21801601 AUTHORS Fogg VC, Lanning NJ, Mackeigan JP TITLE Mitochondria in cancer: at the crossroads of life and death. JOURNAL Chin J Cancer 30:526-39 (2011) DOI:10.5732/cjc.011.10018 REFERENCE PMID:16982728 AUTHORS Kim JW, Dang CV TITLE Cancer's molecular sweet tooth and the Warburg effect. JOURNAL Cancer Res 66:8927-30 (2006) DOI:10.1158/0008-5472.CAN-06-1501 REFERENCE PMID:18766298 AUTHORS Yeung SJ, Pan J, Lee MH TITLE Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. JOURNAL Cell Mol Life Sci 65:3981-99 (2008) DOI:10.1007/s00018-008-8224-x REFERENCE PMID:23897900 AUTHORS Li B, Simon MC TITLE Molecular Pathways: Targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. JOURNAL Clin Cancer Res 19:5835-41 (2013) DOI:10.1158/1078-0432.CCR-12-3629 REFERENCE PMID:22307140 AUTHORS Shen L, Sun X, Fu Z, Yang G, Li J, Yao L TITLE The fundamental role of the p53 pathway in tumor metabolism and its implication in tumor therapy. JOURNAL Clin Cancer Res 18:1561-7 (2012) DOI:10.1158/1078-0432.CCR-11-3040 REFERENCE PMID:19270154 AUTHORS Jones RG, Thompson CB TITLE Tumor suppressors and cell metabolism: a recipe for cancer growth. JOURNAL Genes Dev 23:537-48 (2009) DOI:10.1101/gad.1756509 REFERENCE PMID:21340684 AUTHORS Maddocks OD, Vousden KH TITLE Metabolic regulation by p53. JOURNAL J Mol Med (Berl) 89:237-45 (2011) DOI:10.1007/s00109-011-0735-5 REFERENCE PMID:22750268 AUTHORS Chen JQ, Russo J TITLE Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. JOURNAL Biochim Biophys Acta 1826:370-84 (2012) DOI:10.1016/j.bbcan.2012.06.004 REFERENCE PMID:20520704 AUTHORS Kaelin WG Jr, Thompson CB TITLE Q&A: Cancer: clues from cell metabolism. JOURNAL Nature 465:562-4 (2010) DOI:10.1038/465562a REFERENCE PMID:24113830 AUTHORS Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G TITLE Metabolic targets for cancer therapy. JOURNAL Nat Rev Drug Discov 12:829-46 (2013) DOI:10.1038/nrd4145 REFERENCE PMID:24738035 AUTHORS Phan LM, Yeung SC, Lee MH TITLE Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. JOURNAL Cancer Biol Med 11:1-19 (2014) DOI:10.7497/j.issn.2095-3941.2014.01.001 REFERENCE PMID:22101401 AUTHORS Icard P, Poulain L, Lincet H TITLE Understanding the central role of citrate in the metabolism of cancer cells. JOURNAL Biochim Biophys Acta 1825:111-6 (2012) DOI:10.1016/j.bbcan.2011.10.007 REFERENCE PMID:22349059 AUTHORS Daye D, Wellen KE TITLE Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. JOURNAL Semin Cell Dev Biol 23:362-9 (2012) DOI:10.1016/j.semcdb.2012.02.002 REFERENCE PMID:23018234 AUTHORS Chiarugi A, Dolle C, Felici R, Ziegler M TITLE The NAD metabolome--a key determinant of cancer cell biology. JOURNAL Nat Rev Cancer 12:741-52 (2012) DOI:10.1038/nrc3340 REFERENCE PMID:24398961 AUTHORS Guarente L TITLE The many faces of sirtuins: Sirtuins and the Warburg effect. JOURNAL Nat Med 20:24-5 (2014) DOI:10.1038/nm.3438 REFERENCE PMID:15916903 AUTHORS Fuchs BC, Bode BP TITLE Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? JOURNAL Semin Cancer Biol 15:254-66 (2005) DOI:10.1016/j.semcancer.2005.04.005 REL_PATHWAY ko00010 Glycolysis / Gluconeogenesis ko00020 Citrate cycle (TCA cycle) ko00030 Pentose phosphate pathway ko00190 Oxidative phosphorylation ko00250 Alanine, aspartate and glutamate metabolism ko00260 Glycine, serine and threonine metabolism ko00330 Arginine and proline metabolism ko01212 Fatty acid metabolism ko04010 MAPK signaling pathway ko04066 HIF-1 signaling pathway ko04150 mTOR signaling pathway ko04151 PI3K-Akt signaling pathway ///