KEGG   PATHWAY: biu05231
Entry
biu05231                    Pathway                                
Name
Choline metabolism in cancer - Bos indicus (zebu cattle)
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
biu05231  Choline metabolism in cancer
biu05231

Organism
Bos indicus (zebu cattle) [GN:biu]
Gene
109559983  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
109578611  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
109558630  LOW QUALITY PROTEIN: platelet-derived growth factor subunit B-like [KO:K17386]
109559825  platelet-derived growth factor subunit B isoform X1 [KO:K17386]
109571395  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
109569805  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
109576048  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
109560475  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
109562197  PDGFRB; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:2.7.10.1]
109574040  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
109566002  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
109564346  SOS2; son of sevenless homolog 2 [KO:K03099]
109560940  GTPase HRas-like [KO:K02833]
109559581  KRAS; GTPase KRas isoform X1 [KO:K07827]
109555890  NRAS; GTPase NRas [KO:K07828]
109576053  RAF1; LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
109564697  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109561751  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
109578667  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109570973  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109565671  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
109565672  ral guanine nucleotide dissociation stimulator-like [KO:K08732]
109561331  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109560650  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553773  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109570696  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
109564977  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
109564980  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
109564981  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
109564982  PLA2G4F; cytosolic phospholipase A2 zeta [KO:K16342] [EC:3.1.1.4]
109559805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109570415  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109557823  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
109574805  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
109561418  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109556345  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109578066  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
109572496  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109570286  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109566571  TSC1; hamartin isoform X1 [KO:K07206]
109578279  TSC2; tuberin isoform X1 [KO:K07207]
109557810  RHEB; GTP-binding protein Rheb [KO:K07208]
109570401  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109554358  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
109573726  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
109553533  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
109555129  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X1 [KO:K00889] [EC:2.7.1.68]
109561764  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:2.7.1.68]
109562486  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:2.7.1.68]
109578192  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
109559531  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
109574290  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
109563830  WASF1; wiskott-Aldrich syndrome protein family member 1 [KO:K05753]
109573135  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
109566837  WASF3; wiskott-Aldrich syndrome protein family member 3 [KO:K06083]
109559035  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
109574235  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
109558091  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
109565747  SLC5A7; high affinity choline transporter 1 [KO:K14387]
109563313  SLC44A1; choline transporter-like protein 1 [KO:K06515]
109561597  SLC44A2; choline transporter-like protein 2 isoform X1 [KO:K15377]
109577431  SLC44A4; choline transporter-like protein 4 [KO:K15377]
109556157  SLC44A5; choline transporter-like protein 5 [KO:K15377]
109556040  SLC44A3; choline transporter-like protein 3 isoform X1 [KO:K15282]
109564097  solute carrier family 22 member 1 isoform X1 [KO:K08198]
109564098  solute carrier family 22 member 2 [KO:K08199]
109563600  SLC22A3; LOW QUALITY PROTEIN: solute carrier family 22 member 3 [KO:K08200]
109561819  SLC22A5; solute carrier family 22 member 5 [KO:K08202]
109560971  SLC22A4; solute carrier family 22 member 4 [KO:K08202]
109554145  CHKA; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
109565231  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
109556235  JUN; transcription factor AP-1 [KO:K04448]
109565363  FOS; proto-oncogene c-Fos [KO:K04379]
109555418  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
109556194  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:2.7.7.15]
109558502  CHPT1; cholinephosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
109567698  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
109556245  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
109574777  PLPP1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:3.1.3.4]
109561957  PLPP2; phospholipid phosphatase 2 isoform X1 [KO:K01080] [EC:3.1.3.4]
109557675  DGKI; LOW QUALITY PROTEIN: diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
109566674  diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:2.7.1.107]
109559384  DGKA; diacylglycerol kinase alpha isoform X1 [KO:K00901] [EC:2.7.1.107]
109557141  DGKG; diacylglycerol kinase gamma [KO:K00901] [EC:2.7.1.107]
109557265  DGKB; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:2.7.1.107]
109573863  DGKE; diacylglycerol kinase epsilon isoform X1 [KO:K00901] [EC:2.7.1.107]
109554875  DGKK; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
109556547  DGKD; diacylglycerol kinase delta isoform X1 [KO:K00901] [EC:2.7.1.107]
109560705  DGKQ; diacylglycerol kinase theta isoform X1 [KO:K00901] [EC:2.7.1.107]
109573366  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
109578560  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
109572998  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
109568508  LYPLA1; acyl-protein thioesterase 1 isoform X1 [KO:K06128] [EC:3.1.1.5]
109567633  GPCPD1; 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
biu00564  Glycerophospholipid metabolism
biu04010  MAPK signaling pathway
biu04150  mTOR signaling pathway
biu04151  PI3K-Akt signaling pathway
biu04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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