KEGG   PATHWAY: nle05230
Entry
nle05230                    Pathway                                
Name
Central carbon metabolism in cancer - Nomascus leucogenys (northern white-cheeked gibbon)
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
nle05230  Central carbon metabolism in cancer
nle05230

Organism
Nomascus leucogenys (northern white-cheeked gibbon) [GN:nle]
Gene
100594511  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
100603133  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X3 [KO:K07593]
100591653  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
100600169  PKM; pyruvate kinase PKM isoform X1 [KO:K00873] [EC:2.7.1.40]
100587584  PDHA1; pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial [KO:K00161] [EC:1.2.4.1]
100595000  PDHA2; pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial isoform X1 [KO:K00161] [EC:1.2.4.1]
100606854  PDHB; pyruvate dehydrogenase E1 component subunit beta, mitochondrial [KO:K00162] [EC:1.2.4.1]
100601990  PDK1; pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1, mitochondrial isoform X1 [KO:K12077] [EC:2.7.11.2]
100583326  TP53; cellular tumor antigen p53 [KO:K04451]
100583707  protein SCO2 homolog, mitochondrial [KO:K23755]
100603949  SLC1A5; neutral amino acid transporter B(0) [KO:K05616]
100604320  SIRT3; NAD-dependent protein deacetylase sirtuin-3, mitochondrial isoform X1 [KO:K11413] [EC:2.3.1.286]
100604263  SLC16A3; monocarboxylate transporter 4 isoform X2 [KO:K08180]
100592506  SIRT6; NAD-dependent protein deacetylase sirtuin-6 isoform X1 [KO:K11416] [EC:2.3.1.286]
100589322  MYC; myc proto-oncogene protein [KO:K04377]
100588621  HIF1A; hypoxia-inducible factor 1-alpha isoform X2 [KO:K08268]
100603893  KIT; mast/stem cell growth factor receptor Kit isoform X3 [KO:K05091] [EC:2.7.10.1]
100597172  MET; hepatocyte growth factor receptor isoform X3 [KO:K05099] [EC:2.7.10.1]
100602103  RET; proto-oncogene tyrosine-protein kinase receptor Ret isoform X1 [KO:K05126] [EC:2.7.10.1]
100597255  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100601700  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:2.7.10.1]
100585466  NTRK1; high affinity nerve growth factor receptor [KO:K03176] [EC:2.7.10.1]
100585046  NTRK3; NT-3 growth factor receptor isoform X1 [KO:K05101] [EC:2.7.10.1]
100603207  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
100597894  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
100602423  FGFR1; fibroblast growth factor receptor 1 isoform X1 [KO:K04362] [EC:2.7.10.1]
100598157  FGFR2; fibroblast growth factor receptor 2 isoform X1 [KO:K05093] [EC:2.7.10.1]
100591839  FGFR3; fibroblast growth factor receptor 3 isoform X1 [KO:K05094] [EC:2.7.10.1]
100589184  FLT3; receptor-type tyrosine-protein kinase FLT3 isoform X1 [KO:K05092] [EC:2.7.10.1]
100595274  HRAS; GTPase HRas isoform X1 [KO:K02833]
100593773  KRAS; GTPase KRas isoform X1 [KO:K07827]
100592103  NRAS; GTPase NRas [KO:K07828]
100582599  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100579506  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100591827  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100600574  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100584480  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100606824  GLS; glutaminase kidney isoform, mitochondrial isoform X1 [KO:K01425] [EC:3.5.1.2]
100583191  GLS2; glutaminase liver isoform, mitochondrial isoform X2 [KO:K01425] [EC:3.5.1.2]
100590496  G6PD; glucose-6-phosphate 1-dehydrogenase isoform X1 [KO:K00036] [EC:1.1.1.49 1.1.1.363]
100591401  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100595917  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
100593006  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100595352  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
100587636  PFKM; ATP-dependent 6-phosphofructokinase, muscle type [KO:K00850] [EC:2.7.1.11]
100582114  ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
100601116  PFKP; ATP-dependent 6-phosphofructokinase, platelet type isoform X1 [KO:K00850] [EC:2.7.1.11]
115833153  PFKL; ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
100587552  PGAM1; phosphoglycerate mutase 1 [KO:K01834] [EC:5.4.2.11]
100588293  PGAM2; phosphoglycerate mutase 2 [KO:K01834] [EC:5.4.2.11]
100586354  L-lactate dehydrogenase A chain-like [KO:K00016] [EC:1.1.1.27]
100579290  L-lactate dehydrogenase A-like 6B [KO:K00016] [EC:1.1.1.27]
100581597  LDHAL6B; L-lactate dehydrogenase A-like 6B [KO:K00016] [EC:1.1.1.27]
100587841  LDHB; L-lactate dehydrogenase B chain isoform X2 [KO:K00016] [EC:1.1.1.27]
100604698  L-lactate dehydrogenase A chain [KO:K00016] [EC:1.1.1.27]
100605915  LDHC; L-lactate dehydrogenase C chain isoform X2 [KO:K00016] [EC:1.1.1.27]
100606586  LDHAL6A; L-lactate dehydrogenase A-like 6A isoform X1 [KO:K00016] [EC:1.1.1.27]
100593459  IDH2; isocitrate dehydrogenase [NADP], mitochondrial [KO:K00031] [EC:1.1.1.42]
100591675  IDH1; isocitrate dehydrogenase [NADP] cytoplasmic [KO:K00031] [EC:1.1.1.42]
100604702  TIGAR; fructose-2,6-bisphosphatase TIGAR [KO:K14634] [EC:3.1.3.46]
100605147  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
100588218  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100580872  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100584384  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100605788  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100591270  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100599301  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100604331  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100587864  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100587109  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100594291  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100581072  SLC7A5; large neutral amino acids transporter small subunit 1 [KO:K13780]
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
  Authors
Soga T
  Title
Cancer metabolism: key players in metabolic reprogramming.
  Journal
Cancer Sci 104:275-81 (2013)
DOI:10.1111/cas.12085
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
Related
pathway
nle00010  Glycolysis / Gluconeogenesis
nle00020  Citrate cycle (TCA cycle)
nle00030  Pentose phosphate pathway
nle00190  Oxidative phosphorylation
nle00250  Alanine, aspartate and glutamate metabolism
nle00260  Glycine, serine and threonine metabolism
nle00330  Arginine and proline metabolism
nle01212  Fatty acid metabolism
nle04010  MAPK signaling pathway
nle04066  HIF-1 signaling pathway
nle04150  mTOR signaling pathway
nle04151  PI3K-Akt signaling pathway
KO pathway
ko05230   
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