KEGG   PATHWAY: ptg05231
Entry
ptg05231                    Pathway                                
Name
Choline metabolism in cancer - Panthera tigris altaica (Amur tiger)
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
ptg05231  Choline metabolism in cancer
ptg05231

Organism
Panthera tigris altaica (Amur tiger) [GN:ptg]
Gene
102948969  PLA2G4A; phospholipase A2 group IVA [KO:K16342] [EC:3.1.1.4]
102949131  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
102949403  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
102949507  PCYT1B; phosphate cytidylyltransferase 1, choline, beta [KO:K00968] [EC:2.7.7.15]
102949853  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
102949957  PDGFD; platelet derived growth factor D [KO:K05450]
102950748  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
102950850  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
102950880  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
102951203  WAS; Wiskott-Aldrich syndrome [KO:K05747]
102951241  HIF1A; hypoxia inducible factor 1 alpha subunit [KO:K08268]
102951759  SLC44A2; solute carrier family 44 member 2 [KO:K15377]
102952119  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
102952137  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
102952142  SLC22A1; solute carrier family 22 member 1 [KO:K08198]
102952372  PIP5K1A; phosphatidylinositol-4-phosphate 5-kinase type 1 alpha [KO:K00889] [EC:2.7.1.68]
102952603  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102952769  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
102952814  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
102952980  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
102952993  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
102953082  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
102953166  CHKB; choline kinase beta [KO:K14156] [EC:2.7.1.32 2.7.1.82]
102953527  DGKH; diacylglycerol kinase eta [KO:K00901] [EC:2.7.1.107]
102953558  SLC44A1; solute carrier family 44 member 1 [KO:K06515]
102953615  DGKB; diacylglycerol kinase beta [KO:K00901] [EC:2.7.1.107]
102953770  TSC1; tuberous sclerosis 1 [KO:K07206]
102954106  LYPLA1; lysophospholipase I [KO:K06128] [EC:3.1.1.5]
102954207  PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
102954757  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
102954999  WASF2; WAS protein family member 2 [KO:K05748]
102955021  DGKZ; diacylglycerol kinase zeta [KO:K00901] [EC:2.7.1.107]
102955413  DGKI; diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
102955434  SLC22A5; solute carrier family 22 member 5 [KO:K08202]
102955481  PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
102955504  RAC3; ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) [KO:K07861]
102955720  SLC22A4; solute carrier family 22 member 4 [KO:K08202]
102955852  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
102955984  SP1; Sp1 transcription factor [KO:K04684]
102956176  TSC2; tuberous sclerosis 2 [KO:K07207]
102956490  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
102956808  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102957350  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
102958125  WASF3; WAS protein family member 3 [KO:K06083]
102958666  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
102958782  PIP5K1C; phosphatidylinositol-4-phosphate 5-kinase type 1 gamma [KO:K00889] [EC:2.7.1.68]
102958925  DGKA; diacylglycerol kinase alpha [KO:K00901] [EC:2.7.1.107]
102959018  PLA2G4B; phospholipase A2 group IVB [KO:K16342] [EC:3.1.1.4]
102959159  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102959553  WASF1; WAS protein family member 1 [KO:K05753]
102959656  EGF; epidermal growth factor [KO:K04357]
102959667  PLA2G4E; phospholipase A2 group IVE [KO:K16342] [EC:3.1.1.4]
102959937  PLA2G4F; phospholipase A2 group IVF [KO:K16342] [EC:3.1.1.4]
102960329  SLC5A7; solute carrier family 5 member 7 [KO:K14387]
102960424  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102960474  DGKQ; diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
102960736  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
102960964  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102961839  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
102961922  RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
102961960  CHPT1; choline phosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
102962016  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
102962329  SLC44A5; solute carrier family 44 member 5 [KO:K15377]
102962574  SLC44A3; solute carrier family 44 member 3 [KO:K15282]
102962708  SLC22A2; solute carrier family 22 member 2 [KO:K08199]
102962986  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
102963006  DGKG; diacylglycerol kinase gamma [KO:K00901] [EC:2.7.1.107]
102963096  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
102964036  PLA2G4D; phospholipase A2 group IVD [KO:K16342] [EC:3.1.1.4]
102964557  PCYT1A; phosphate cytidylyltransferase 1, choline, alpha [KO:K00968] [EC:2.7.7.15]
102964841  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102965070  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
102965767  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
102966331  PIP5K1B; phosphatidylinositol-4-phosphate 5-kinase type 1 beta [KO:K00889] [EC:2.7.1.68]
102966968  GPCPD1; glycerophosphocholine phosphodiesterase 1 [KO:K18695] [EC:3.1.4.2]
102967196  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
102967370  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102967709  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
102968561  RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
102968590  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
102969217  CHKA; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
102969757  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102970146  RHEB; Ras homolog enriched in brain [KO:K07208]
102970459  GRB2; growth factor receptor bound protein 2 [KO:K04364]
102970516  SLC44A4; solute carrier family 44 member 4 [KO:K15377]
102970530  PDGFC; platelet derived growth factor C [KO:K05450]
102971423  DGKK; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
102971478  PLPP1; phospholipid phosphatase 1 [KO:K01080] [EC:3.1.3.4]
102971527  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
102971652  PLPP2; phospholipid phosphatase 2 [KO:K01080] [EC:3.1.3.4]
102971823  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
102971867  PDGFB; platelet derived growth factor subunit B [KO:K17386]
102972280  DGKD; diacylglycerol kinase delta [KO:K00901] [EC:2.7.1.107]
102972487  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
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
ptg00564  Glycerophospholipid metabolism
ptg04010  MAPK signaling pathway
ptg04150  mTOR signaling pathway
ptg04151  PI3K-Akt signaling pathway
ptg04810  Regulation of actin cytoskeleton
KO pathway
ko05231   

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