KEGG   PATHWAY: caty05231
Entry
caty05231                   Pathway                                
Name
Choline metabolism in cancer - Cercocebus atys (sooty mangabey)
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
caty05231  Choline metabolism in cancer
caty05231

Organism
Cercocebus atys (sooty mangabey) [GN:caty]
Gene
105571434  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
105571784  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
105572960  PDGFB; platelet-derived growth factor subunit B isoform X1 [KO:K17386]
105588762  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
105597890  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
105588269  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
105592013  PDGFRA; LOW QUALITY PROTEIN: platelet-derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
105589876  PDGFRB; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:2.7.10.1]
105577731  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
105586728  SOS2; son of sevenless homolog 2 [KO:K03099]
105597205  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105577198  HRAS; GTPase HRas isoform X1 [KO:K02833]
105585038  KRAS; GTPase KRas isoform X1 [KO:K07827]
105596344  NRAS; GTPase NRas isoform X1 [KO:K07828]
105585803  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105601165  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105591800  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
105598233  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105598850  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
105594177  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
105575634  LOW QUALITY PROTEIN: ral-GDS-related protein-like [KO:K08732]
105575857  ral-GDS-related protein-like [KO:K08732]
105599414  LOW QUALITY PROTEIN: ral-GDS-related protein-like [KO:K08732]
105590417  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105591436  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105576775  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105579889  PLA2G4A; cytosolic phospholipase A2 isoform X1 [KO:K16342] [EC:3.1.1.4]
105595443  PLA2G4C; cytosolic phospholipase A2 gamma [KO:K16342] [EC:3.1.1.4]
105574211  PLA2G4B; cytosolic phospholipase A2 beta isoform X1 [KO:K16342] [EC:3.1.1.4]
105574213  PLA2G4E; cytosolic phospholipase A2 epsilon isoform X1 [KO:K16342] [EC:3.1.1.4]
105574214  PLA2G4F; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
105574265  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
105586383  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105580892  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105597716  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105571321  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105594576  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105599262  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105573290  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105596769  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105597977  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105574942  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105594171  TSC1; hamartin isoform X1 [KO:K07206]
105573530  TSC2; tuberin isoform X1 [KO:K07207]
105584756  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
105580870  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
105577354  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
105583339  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105590788  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105590224  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X1 [KO:K00889] [EC:2.7.1.68]
105584145  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:2.7.1.68]
105591788  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:2.7.1.68]
105573131  WAS; wiskott-Aldrich syndrome protein [KO:K05747]
105584356  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
105575821  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
105588572  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
105581361  WASF1; wiskott-Aldrich syndrome protein family member 1 [KO:K05753]
105594901  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
105597042  WASF3; wiskott-Aldrich syndrome protein family member 3 isoform X1 [KO:K06083]
105580268  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
105586073  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
105583465  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
105583605  SLC5A7; high affinity choline transporter 1 [KO:K14387]
105572383  SLC44A1; choline transporter-like protein 1 [KO:K06515]
105601454  SLC44A2; choline transporter-like protein 2 isoform X1 [KO:K15377]
105595846  SLC44A5; choline transporter-like protein 5 isoform X1 [KO:K15377]
105573426  SLC44A4; choline transporter-like protein 4 [KO:K15377]
105589431  SLC44A3; choline transporter-like protein 3 isoform X1 [KO:K15282]
105581317  SLC22A1; LOW QUALITY PROTEIN: solute carrier family 22 member 1 [KO:K08198]
105581316  SLC22A2; LOW QUALITY PROTEIN: solute carrier family 22 member 2 [KO:K08199]
105581313  SLC22A3; solute carrier family 22 member 3 isoform X1 [KO:K08200]
105599734  SLC22A4; solute carrier family 22 member 4 isoform X1 [KO:K08202]
105599736  SLC22A5; solute carrier family 22 member 5 isoform X1 [KO:K08202]
105577333  CHKA; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105586863  CHKB; choline/ethanolamine kinase [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105586718  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
105595973  JUN; transcription factor AP-1 [KO:K04448]
105590868  FOS; proto-oncogene c-Fos [KO:K04379]
105574608  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
105575118  PCYT1A; choline-phosphate cytidylyltransferase A isoform X1 [KO:K00968] [EC:2.7.7.15]
105573314  CHPT1; cholinephosphotransferase 1 isoform X1 [KO:K00994] [EC:2.7.8.2]
105588401  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
105595985  PPAP2B; lipid phosphate phosphohydrolase 3 [KO:K01080] [EC:3.1.3.4]
105597707  PPAP2A; lipid phosphate phosphohydrolase 1 isoform X1 [KO:K01080] [EC:3.1.3.4]
105591665  PPAP2C; lipid phosphate phosphohydrolase 2 isoform X1 [KO:K01080] [EC:3.1.3.4]
105592794  DGKZ; diacylglycerol kinase zeta isoform X1 [KO:K00901] [EC:2.7.1.107]
105585504  DGKQ; diacylglycerol kinase theta isoform X1 [KO:K00901] [EC:2.7.1.107]
105587318  DGKA; diacylglycerol kinase alpha isoform X1 [KO:K00901] [EC:2.7.1.107]
105571913  DGKK; diacylglycerol kinase kappa isoform X1 [KO:K00901] [EC:2.7.1.107]
105587814  DGKH; diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:2.7.1.107]
105589572  DGKB; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:2.7.1.107]
105589636  DGKI; diacylglycerol kinase iota isoform X1 [KO:K00901] [EC:2.7.1.107]
105573940  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:2.7.1.107]
105583288  DGKE; diacylglycerol kinase epsilon isoform X1 [KO:K00901] [EC:2.7.1.107]
105591642  DGKD; diacylglycerol kinase delta isoform X1 [KO:K00901] [EC:2.7.1.107]
105599331  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105586076  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
105595654  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105592144  LYPLA1; acyl-protein thioesterase 1 isoform X1 [KO:K06128] [EC:3.1.1.5]
105582107  GPCPD1; LOW QUALITY PROTEIN: glycerophosphocholine phosphodiesterase GPCPD1 [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
caty00564  Glycerophospholipid metabolism
caty04010  MAPK signaling pathway
caty04150  mTOR signaling pathway
caty04151  PI3K-Akt signaling pathway
caty04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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