KEGG   PATHWAY: shr05231
Entry
shr05231                    Pathway                                
Name
Choline metabolism in cancer - Sarcophilus harrisii (Tasmanian devil)
Description
Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.
Class
Human Diseases; Cancer: overview
Pathway map
shr05231  Choline metabolism in cancer
shr05231

Organism
Sarcophilus harrisii (Tasmanian devil) [GN:shr]
Gene
100933169  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
100924985  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
116422035  platelet-derived growth factor subunit A-like [KO:K04359]
100917875  PDGFB; platelet-derived growth factor subunit B isoform X2 [KO:K17386]
100928148  PDGFC; platelet-derived growth factor C [KO:K05450]
100916102  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
100914017  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100925116  PDGFRA; platelet-derived growth factor receptor alpha isoform X2 [KO:K04363] [EC:2.7.10.1]
100917212  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
100928380  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100931009  SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]
100932999  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100929168  ras-like protein [KO:K02833]
116419913  HRAS; GTPase HRas [KO:K02833]
100915526  KRAS; GTPase KRas isoform X1 [KO:K07827]
100927252  ras-related protein Rab-26-like [KO:K07827]
100929426  ras protein let-60-like [KO:K07827]
100928986  NRAS; GTPase NRas [KO:K07828]
100935202  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
100921899  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
100917396  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
100934330  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100913231  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100917637  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
100930815  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100928480  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100924267  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100927268  PLA2G4A; cytosolic phospholipase A2 isoform X1 [KO:K16342] [EC:3.1.1.4]
100913647  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
100927005  PLA2G4C; cytosolic phospholipase A2 gamma isoform X1 [KO:K16342] [EC:3.1.1.4]
100914602  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
100917893  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
100918158  PLA2G4F; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
100929811  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100932099  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105749979  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100926892  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100924976  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
100935230  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100917568  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100917987  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100913262  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100925440  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100918165  TSC1; hamartin isoform X1 [KO:K07206]
100918445  TSC2; tuberin isoform X1 [KO:K07207]
100919006  RHEB; GTP-binding protein Rheb [KO:K07208]
100931480  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100935081  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100930707  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X2 [KO:K04688] [EC:2.7.11.1]
100918487  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
111718631  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100918263  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:2.7.1.68]
100925674  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta isoform X1 [KO:K00889] [EC:2.7.1.68]
100930714  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha [KO:K00889] [EC:2.7.1.68]
100934222  WAS; wiskott-Aldrich syndrome protein [KO:K05747]
100919657  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
100932383  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
100924669  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
100921263  WASF1; wiskott-Aldrich syndrome protein family member 1 isoform X1 [KO:K05753]
100927851  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
100924737  WASF3; wiskott-Aldrich syndrome protein family member 3 isoform X2 [KO:K06083]
100934823  LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein family member 3-like [KO:K06083]
100930024  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
100926651  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
100914579  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100933217  high affinity choline transporter 1 [KO:K14387]
105750245  LOW QUALITY PROTEIN: high affinity choline transporter 1-like [KO:K14387]
100922191  SLC44A1; choline transporter-like protein 1 isoform X1 [KO:K06515]
100926365  SLC44A2; choline transporter-like protein 2 isoform X5 [KO:K15377]
100930884  SLC44A4; choline transporter-like protein 4 isoform X2 [KO:K15377]
100928135  SLC44A5; choline transporter-like protein 5 [KO:K15377]
100929501  SLC44A3; choline transporter-like protein 3 isoform X1 [KO:K15282]
100927176  solute carrier family 22 member 1 [KO:K08198]
100927429  SLC22A2; solute carrier family 22 member 2 [KO:K08199]
100927691  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
100933352  SLC22A4; solute carrier family 22 member 4 isoform X1 [KO:K08202]
100914422  solute carrier family 22 member 5 isoform X1 [KO:K08202]
100931939  CHKB; choline/ethanolamine kinase isoform X1 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
100917717  CHKA; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
100931887  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
116423739  JUN; transcription factor AP-1 [KO:K04448]
100924435  FOS; proto-oncogene c-Fos [KO:K04379]
100917669  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:2.7.7.15]
100923586  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
116419654  CHPT1; cholinephosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
100923119  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100934490  PLPP1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:3.1.3.4]
100926398  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
100927244  PLPP2; phospholipid phosphatase 2 [KO:K01080] [EC:3.1.3.4]
111719176  phospholipid phosphatase 3-like [KO:K01080] [EC:3.1.3.4]
100915354  DGKD; LOW QUALITY PROTEIN: diacylglycerol kinase delta [KO:K00901] [EC:2.7.1.107]
100924148  DGKG; diacylglycerol kinase gamma [KO:K00901] [EC:2.7.1.107]
100926156  DGKI; diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
100921952  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
100922152  DGKQ; diacylglycerol kinase theta isoform X1 [KO:K00901] [EC:2.7.1.107]
100934372  DGKB; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:2.7.1.107]
100922813  DGKH; diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:2.7.1.107]
100926158  DGKA; diacylglycerol kinase alpha isoform X1 [KO:K00901] [EC:2.7.1.107]
100924793  DGKK; diacylglycerol kinase kappa isoform X1 [KO:K00901] [EC:2.7.1.107]
100914407  DGKZ; diacylglycerol kinase zeta [KO:K00901] [EC:2.7.1.107]
100913337  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100924022  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100935225  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100924992  LYPLA1; acyl-protein thioesterase 1 isoform X1 [KO:K06128] [EC:3.1.1.5]
100923561  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 isoform X1 [KO:K18695] [EC:3.1.4.2]
Compound
C00093  sn-Glycerol 3-phosphate
C00114  Choline
C00157  Phosphatidylcholine
C00162  Fatty acid
C00165  Diacylglycerol
C00307  CDP-choline
C00416  Phosphatidate
C00588  Choline phosphate
C00670  sn-Glycero-3-phosphocholine
C04230  1-Acyl-sn-glycero-3-phosphocholine
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:22089420
  Authors
Glunde K, Bhujwalla ZM, Ronen SM
  Title
Choline metabolism in malignant transformation.
  Journal
Nat Rev Cancer 11:835-48 (2011)
DOI:10.1038/nrc3162
Reference
PMID:19935796
  Authors
Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO
  Title
Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy.
  Journal
Br J Cancer 102:1-7 (2010)
DOI:10.1038/sj.bjc.6605457
Reference
PMID:22429397
  Authors
Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F
  Title
Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.
  Journal
Breast Cancer Res 14:R50 (2012)
DOI:10.1186/bcr3151
Reference
PMID:19264150
  Authors
Foster DA
  Title
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
  Journal
Biochim Biophys Acta 1791:949-55 (2009)
DOI:10.1016/j.bbalip.2009.02.009
Reference
PMID:16432178
  Authors
Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM
  Title
Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
  Journal
Mol Cancer Ther 5:187-96 (2006)
DOI:10.1158/1535-7163.MCT-03-0220
Reference
PMID:23350810
  Authors
Ridgway ND
  Title
The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.
  Journal
Crit Rev Biochem Mol Biol 48:20-38 (2013)
DOI:10.3109/10409238.2012.735643
Reference
PMID:22921309
  Authors
Awwad HM, Geisel J, Obeid R
  Title
The role of choline in prostate cancer.
  Journal
Clin Biochem 45:1548-53 (2012)
DOI:10.1016/j.clinbiochem.2012.08.012
Reference
PMID:16230400
  Authors
Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D'Ascenzo S, Millimaggi D, Pavan A, Dolo V, Canevari S, Podo F
  Title
Alterations of choline phospholipid metabolism in ovarian tumor progression.
  Journal
Cancer Res 65:9369-76 (2005)
DOI:10.1158/0008-5472.CAN-05-1146
Reference
PMID:14523987
  Authors
Ackerstaff E, Glunde K, Bhujwalla ZM
  Title
Choline phospholipid metabolism: a target in cancer cells?
  Journal
J Cell Biochem 90:525-33 (2003)
DOI:10.1002/jcb.10659
Reference
PMID:23076158
  Authors
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
  Title
Phospholipase signalling networks in cancer.
  Journal
Nat Rev Cancer 12:782-92 (2012)
DOI:10.1038/nrc3379
Reference
PMID:19855431
  Authors
Yalcin A, Clem B, Makoni S, Clem A, Nelson K, Thornburg J, Siow D, Lane AN, Brock SE, Goswami U, Eaton JW, Telang S, Chesney J
  Title
Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.
  Journal
Oncogene 29:139-49 (2010)
DOI:10.1038/onc.2009.317
Reference
PMID:21793073
  Authors
Glunde K, Jiang L, Moestue SA, Gribbestad IS
  Title
MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer.
  Journal
NMR Biomed 24:673-90 (2011)
DOI:10.1002/nbm.1751
Reference
PMID:19136975
  Authors
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
  Title
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
  Journal
Nat Chem Biol 5:108-17 (2009)
DOI:10.1038/nchembio.140
Reference
PMID:14517341
  Authors
Foster DA, Xu L
  Title
Phospholipase D in cell proliferation and cancer.
  Journal
Mol Cancer Res 1:789-800 (2003)
Reference
PMID:20528734
  Authors
Zhou H, Huang S
  Title
mTOR signaling in cancer cell motility and tumor metastasis.
  Journal
Crit Rev Eukaryot Gene Expr 20:1-16 (2010)
DOI:10.1615/critreveukargeneexpr.v20.i1.10
Related
pathway
shr00564  Glycerophospholipid metabolism
shr04010  MAPK signaling pathway
shr04150  mTOR signaling pathway
shr04151  PI3K-Akt signaling pathway
shr04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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