KEGG   PATHWAY: bta05231
Entry
bta05231                    Pathway                                
Name
Choline metabolism in cancer - Bos taurus (cow)
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
bta05231  Choline metabolism in cancer
bta05231

Organism
Bos taurus (cow) [GN:bta]
Gene
530315  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
505908  PDGFA; platelet-derived growth factor subunit A precursor [KO:K04359]
540106  PDGFB; platelet-derived growth factor subunit B precursor [KO:K17386]
613787  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
525931  PDGFD; platelet-derived growth factor D [KO:K05450]
407217  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
282301  PDGFRA; platelet-derived growth factor receptor alpha precursor [KO:K04363] [EC:2.7.10.1]
527165  PDGFRB; platelet-derived growth factor receptor beta precursor [KO:K05089] [EC:2.7.10.1]
535298  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
537682  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100138040  SOS2; son of sevenless homolog 2 [KO:K03099]
100298939  HRAS; GTPase HRas isoform 1 [KO:K02833]
100847184  GTPase HRas-like [KO:K02833]
541140  KRAS; GTPase KRas [KO:K07827]
506322  NRAS; GTPase NRas [KO:K07828]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101905399  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
513723  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
526364  PLA2G4E; cytosolic phospholipase A2 epsilon isoform X1 [KO:K16342] [EC:3.1.1.4]
505485  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
522866  PLA2G4F; cytosolic phospholipase A2 zeta [KO:K16342] [EC:3.1.1.4]
531209  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
525072  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100138102  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
533440  TSC1; hamartin isoform X1 [KO:K07206]
504985  TSC2; tuberin isoform X9 [KO:K07207]
528204  RHEB; GTP-binding protein Rheb [KO:K07208]
100139219  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
404181  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
506083  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
509613  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
508819  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma [KO:K00889] [EC:2.7.1.68]
100125224  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha [KO:K00889] [EC:2.7.1.68]
537654  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta isoform X5 [KO:K00889] [EC:2.7.1.68]
107131173  WAS; actin nucleation-promoting factor WAS [KO:K05747]
281440  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
327671  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
619066  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
531488  WASF1; actin-binding protein WASF1 [KO:K05753]
504482  WASF2; actin-binding protein WASF2 [KO:K05748]
540674  WASF3; actin-binding protein WASF3 [KO:K06083]
540741  SP1; transcription factor Sp1 [KO:K04684]
522159  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
514554  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
512311  SLC5A7; high affinity choline transporter 1 [KO:K14387]
538887  SLC44A1; choline transporter-like protein 1 isoform X2 [KO:K06515]
520625  SLC44A4; choline transporter-like protein 4 [KO:K15377]
530146  SLC44A5; choline transporter-like protein 5 [KO:K15377]
617624  SLC44A2; choline transporter-like protein 2 [KO:K15377]
507455  SLC44A3; choline transporter-like protein 3 [KO:K15282]
519461  SLC22A1; solute carrier family 22 member 1 [KO:K08198]
521027  SLC22A2; solute carrier family 22 member 2 isoform X1 [KO:K08199]
535665  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
541266  SLC22A5; organic cation/carnitine transporter 2 [KO:K08202]
508155  SLC22A4; solute carrier family 22 member 4 [KO:K08202]
514865  CHKA; choline kinase alpha isoform X1 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
536213  CHKB; choline/ethanolamine kinase [KO:K14156] [EC:2.7.1.32 2.7.1.82]
281814  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
280831  JUN; transcription factor Jun [KO:K04448]
280795  FOS; protein c-Fos [KO:K04379]
100125779  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:2.7.7.15]
526175  PCYT1B; choline-phosphate cytidylyltransferase B [KO:K00968] [EC:2.7.7.15]
511291  CHPT1; cholinephosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
281987  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
504545  PLPP2; phospholipid phosphatase 2 precursor [KO:K01080] [EC:3.1.3.4]
617707  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
617172  PLPP1; phospholipid phosphatase 1 [KO:K01080] [EC:3.1.3.4]
101905992  uncharacterized protein LOC101905992 isoform X1 [KO:K01080] [EC:3.1.3.4]
537171  DGKB; diacylglycerol kinase beta [KO:K00901] [EC:2.7.1.107]
538147  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
518371  DGKQ; diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
530095  DGKI; diacylglycerol kinase iota isoform X1 [KO:K00901] [EC:2.7.1.107]
513389  DGKD; diacylglycerol kinase delta [KO:K00901] [EC:2.7.1.107]
537533  DGKH; diacylglycerol kinase eta isoform X4 [KO:K00901] [EC:2.7.1.107]
506348  DGKA; diacylglycerol kinase alpha [KO:K00901] [EC:2.7.1.107]
518523  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:2.7.1.107]
511887  DGKZ; diacylglycerol kinase zeta [KO:K00901] [EC:2.7.1.107]
107132066  DGKK; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
282001  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
282325  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
282002  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
539992  LYPLA1; acyl-protein thioesterase 1 [KO:K06128] [EC:3.1.1.5]
782114  acyl-protein thioesterase 1 [KO:K06128] [EC:3.1.1.5]
518469  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 isoform X2 [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
bta00564  Glycerophospholipid metabolism
bta04010  MAPK signaling pathway
bta04150  mTOR signaling pathway
bta04151  PI3K-Akt signaling pathway
bta04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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