KEGG   PATHWAY: pon05231
pon05231                    Pathway                                

Choline metabolism in cancer - Pongo abelii (Sumatran orangutan)
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.
Human Diseases; Cancer: overview
Pathway map
pon05231  Choline metabolism in cancer

Pongo abelii (Sumatran orangutan) [GN:pon]
100455021  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
100440212  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
100460243  PDGFB; platelet-derived growth factor subunit B [KO:K17386]
100437861  PDGFC; platelet-derived growth factor C [KO:K05450]
100172718  PDGFD; platelet-derived growth factor D precursor [KO:K05450]
100459280  EGFR; epidermal growth factor receptor isoform X2 [KO:K04361] [EC:]
100431735  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:]
100460001  PDGFRB; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:]
100173972  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100434331  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100458733  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100459427  HRAS; GTPase HRas [KO:K02833]
100462513  KRAS; GTPase KRas isoform X1 [KO:K07827]
100174317  NRAS; GTPase NRas precursor [KO:K07828]
100173732  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
100446021  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
100450988  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
100169740  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:]
100431824  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:]
100451493  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
100434751  LOW QUALITY PROTEIN: ral-GDS-related protein [KO:K08732]
100174482  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
100459133  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:]
100437424  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:]
100454614  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:]
100173125  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:]
100447631  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:]
100434495  PLA2G4C; cytosolic phospholipase A2 gamma isoform X3 [KO:K16342] [EC:]
100454977  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:]
100448616  PLA2G4F; cytosolic phospholipase A2 zeta [KO:K16342] [EC:]
100432846  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
100453779  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
103889133  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
100174298  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100173589  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100437617  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100452403  LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:]
112129400  LOW QUALITY PROTEIN: putative 3-phosphoinositide-dependent protein kinase 2 [KO:K06276] [EC:]
100454279  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100448114  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
100442100  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100147742  TSC1; hamartin [KO:K07206]
100441126  TSC2; tuberin isoform X1 [KO:K07207]
100447214  RHEB; GTP-binding protein Rheb [KO:K07208]
100456786  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
100462008  LOW QUALITY PROTEIN: ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:]
100459428  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:]
100456988  RPS6KB1; LOW QUALITY PROTEIN: ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:]
100455169  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100456775  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X3 [KO:K00889] [EC:]
100432274  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:]
100435603  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:]
100443776  putative PIP5K1A and PSMD4-like protein [KO:K00889] [EC:]
100444466  phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X1 [KO:K00889] [EC:]
100452449  WAS; LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein [KO:K05747]
100443271  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100431483  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
112129584  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
100174148  WASF1; wiskott-Aldrich syndrome protein family member 1 [KO:K05753]
100437132  LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein family member 2-like [KO:K05748]
100447501  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
100445243  WASF3; wiskott-Aldrich syndrome protein family member 3 isoform X1 [KO:K06083]
100440745  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
100439813  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:]
100457163  PLD2; phospholipase D2 [KO:K01115] [EC:]
100457648  SLC5A7; high affinity choline transporter 1 isoform X1 [KO:K14387]
100449286  SLC44A1; choline transporter-like protein 1 isoform X1 [KO:K06515]
100171495  SLC44A4; choline transporter-like protein 4 [KO:K15377]
100443199  SLC44A5; choline transporter-like protein 5 isoform X1 [KO:K15377]
100173738  SLC44A2; choline transporter-like protein 2 [KO:K15377]
100455825  SLC44A3; choline transporter-like protein 3 isoform X1 [KO:K15282]
100436901  SLC22A1; solute carrier family 22 member 1 isoform X1 [KO:K08198]
100173770  SLC22A2; solute carrier family 22 member 2 [KO:K08199]
100438264  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
100449383  SLC22A5; solute carrier family 22 member 5 isoform X1 [KO:K08202]
100456472  SLC22A4; solute carrier family 22 member 4 isoform X1 [KO:K08202]
100445305  CHKB; choline/ethanolamine kinase [KO:K14156] [EC:]
100451626  CHKA; choline kinase alpha isoform X1 [KO:K14156] [EC:]
100173994  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
100450292  JUN; transcription factor AP-1 [KO:K04448]
100462290  FOS; proto-oncogene c-Fos [KO:K04379]
100435111  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:]
100462209  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:]
100440613  CHPT1; cholinephosphotransferase 1 [KO:K00994] [EC:]
100450941  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:]
100442989  PLPP2; phospholipid phosphatase 2 isoform X1 [KO:K01080] [EC:]
100448168  PLPP1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:]
100455097  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:]
100431923  DGKZ; diacylglycerol kinase zeta isoform X1 [KO:K00901] [EC:]
100172456  DGKA; diacylglycerol kinase alpha [KO:K00901] [EC:]
100457783  DGKQ; diacylglycerol kinase theta [KO:K00901] [EC:]
100438777  DGKH; diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:]
100446422  DGKD; diacylglycerol kinase delta isoform X1 [KO:K00901] [EC:]
100460596  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:]
100439722  DGKB; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:]
100440522  DGKE; diacylglycerol kinase epsilon isoform X2 [KO:K00901] [EC:]
100439951  DGKK; diacylglycerol kinase kappa isoform X1 [KO:K00901] [EC:]
100452590  DGKI; LOW QUALITY PROTEIN: diacylglycerol kinase iota [KO:K00901] [EC:]
100434355  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:]
100439900  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:]
100451563  PRKCG; protein kinase C gamma type [KO:K19663] [EC:]
100172358  LYPLA1; acyl-protein thioesterase 1 [KO:K06128] [EC:]
100457313  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 isoform X1 [KO:K18695] [EC:]
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
Glunde K, Bhujwalla ZM, Ronen SM
Choline metabolism in malignant transformation.
Nat Rev Cancer 11:835-48 (2011)
Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO
Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy.
Br J Cancer 102:1-7 (2010)
Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F
Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.
Breast Cancer Res 14:R50 (2012)
Foster DA
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
Biochim Biophys Acta 1791:949-55 (2009)
Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM
Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
Mol Cancer Ther 5:187-96 (2006)
Ridgway ND
The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.
Crit Rev Biochem Mol Biol 48:20-38 (2013)
Awwad HM, Geisel J, Obeid R
The role of choline in prostate cancer.
Clin Biochem 45:1548-53 (2012)
Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D'Ascenzo S, Millimaggi D, Pavan A, Dolo V, Canevari S, Podo F
Alterations of choline phospholipid metabolism in ovarian tumor progression.
Cancer Res 65:9369-76 (2005)
Ackerstaff E, Glunde K, Bhujwalla ZM
Choline phospholipid metabolism: a target in cancer cells?
J Cell Biochem 90:525-33 (2003)
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
Phospholipase signalling networks in cancer.
Nat Rev Cancer 12:782-92 (2012)
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
Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.
Oncogene 29:139-49 (2010)
Glunde K, Jiang L, Moestue SA, Gribbestad IS
MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer.
NMR Biomed 24:673-90 (2011)
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
Nat Chem Biol 5:108-17 (2009)
Foster DA, Xu L
Phospholipase D in cell proliferation and cancer.
Mol Cancer Res 1:789-800 (2003)
Zhou H, Huang S
mTOR signaling in cancer cell motility and tumor metastasis.
Crit Rev Eukaryot Gene Expr 20:1-16 (2010)
pon00564  Glycerophospholipid metabolism
pon04010  MAPK signaling pathway
pon04150  mTOR signaling pathway
pon04151  PI3K-Akt signaling pathway
pon04810  Regulation of actin cytoskeleton
KO pathway

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