KEGG   PATHWAY: ko05231
Entry
ko05231                     Pathway                                
Name
Choline metabolism in cancer
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
ko05231  Choline metabolism in cancer
ko05231

Orthology
K00889  PIP5K; 1-phosphatidylinositol-4-phosphate 5-kinase [EC:2.7.1.68]
K00901  dgkA, DGK; diacylglycerol kinase (ATP) [EC:2.7.1.107]
K00922  PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K00968  PCYT1; choline-phosphate cytidylyltransferase [EC:2.7.7.15]
K00994  CHPT1, CPT1; diacylglycerol cholinephosphotransferase [EC:2.7.8.2]
K01080  PLPP1_2_3; phosphatidate phosphatase [EC:3.1.3.4]
K01115  PLD1_2; phospholipase D1/2 [EC:3.1.4.4]
K01116  PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K02649  PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K03099  SOS; son of sevenless
K04357  EGF; epidermal growth factor
K04359  PDGFA; platelet-derived growth factor subunit A
K04361  EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]
K04363  PDGFRA, CD140A; platelet-derived growth factor receptor alpha [EC:2.7.10.1]
K04364  GRB2; growth factor receptor-bound protein 2
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04379  FOS; proto-oncogene protein c-fos
K04392  RAC1; Ras-related C3 botulinum toxin substrate 1
K04440  JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04448  JUN; transcription factor AP-1
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04684  SP1; transcription factor Sp1
K04688  RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]
K05089  PDGFRB, CD140B; platelet-derived growth factor receptor beta [EC:2.7.10.1]
K05450  PDGFC_D; platelet derived growth factor C/D
K05747  WAS; Wiskott-Aldrich syndrome protein
K05748  WASF2; WAS protein family, member 2
K05753  WASF1; WAS protein family, member 1
K06083  WASF3; WAS protein family, member 3
K06128  LYPLA1; lysophospholipase I [EC:3.1.1.5]
K06276  PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K06515  SLC44A1, CD92; solute carrier family 44 (choline transporter-like protein), member 1
K07203  MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07205  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1
K07206  TSC1; tuberous sclerosis 1
K07207  TSC2; tuberous sclerosis 2
K07208  RHEB; Ras homolog enriched in brain
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K07860  RAC2; Ras-related C3 botulinum toxin substrate 2
K07861  RAC3; Ras-related C3 botulinum toxin substrate 3
K08198  SLC22A1, OCT1; MFS transporter, OCT family, solute carrier family 22 (organic cation transporter), member 1
K08199  SLC22A2, OCT2; MFS transporter, OCT family, solute carrier family 22 (organic cation transporter), member 2
K08200  SLC22A3, OCT3; MFS transporter, OCT family, solute carrier family 22 (organic cation transporter), member 3
K08202  SLC22A4_5, OCTN; MFS transporter, OCT family, solute carrier family 22 (organic cation transporter), member 4/5
K08268  HIF1A; hypoxia-inducible factor 1 alpha
K08732  RALGDS; ral guanine nucleotide dissociation stimulator
K14156  CHK; choline/ethanolamine kinase [EC:2.7.1.32 2.7.1.82]
K14387  SLC5A7, CHT1; solute carrier family 5 (high affinity choline transporter), member 7
K15282  SLC44A3; solute carrier family 44 (choline transporter-like protein), member 3
K15377  SLC44A2_4_5; solute carrier family 44 (choline transporter-like protein), member 2/4/5
K16342  PLA2G4, CPLA2; cytosolic phospholipase A2 [EC:3.1.1.4]
K17386  PDGFB; platelet-derived growth factor subunit B
K18695  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 [EC:3.1.4.2]
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
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
ko00564  Glycerophospholipid metabolism
ko04010  MAPK signaling pathway
ko04150  mTOR signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04810  Regulation of actin cytoskeleton

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