KEGG   PATHWAY: mcc05231
mcc05231                    Pathway                                

Choline metabolism in cancer - Macaca mulatta (rhesus monkey)
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.
Human Diseases; Cancer: overview
Pathway map
mcc05231  Choline metabolism in cancer

Macaca mulatta (rhesus monkey) [GN:mcc]
698619  EGF; pro-epidermal growth factor isoform X2 [KO:K04357]
707725  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
703173  PDGFB; platelet-derived growth factor subunit B [KO:K17386]
704310  PDGFD; platelet-derived growth factor D isoform X2 [KO:K05450]
700236  PDGFC; platelet-derived growth factor C [KO:K05450]
613027  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:]
697002  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:]
711353  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:]
702041  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
713777  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
705601  SOS2; son of sevenless homolog 2 [KO:K03099]
698830  HRAS; GTPase HRas [KO:K02833]
707977  KRAS; GTPase KRas [KO:K07827]
709089  NRAS; GTPase NRas [KO:K07828]
694725  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
710415  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
721821  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
708938  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
698569  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
714436  RALGDS; ral guanine nucleotide dissociation stimulator isoform X4 [KO:K08732]
710293  ral-GDS-related protein isoform X2 [KO:K08732]
711158  ral-GDS-related protein-like isoform X1 [KO:K08732]
114670406  ral-GDS-related protein-like isoform X1 [KO:K08732]
100426259  ral-GDS-related protein-like [KO:K08732]
106992479  ral-GDS-related protein-like [KO:K08732]
106995524  ral-GDS-related protein-like isoform X1 [KO:K08732]
710997  ral-GDS-related protein-like isoform X1 [KO:K08732]
106995478  ral-GDS-related protein-like isoform X1 [KO:K08732]
699736  MAPK10; mitogen-activated protein kinase 10 isoform 1 [KO:K04440] [EC:]
711115  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:]
715782  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:]
716635  PLA2G4A; cytosolic phospholipase A2 isoform X1 [KO:K16342] [EC:]
100533113  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:]
718510  cytosolic phospholipase A2 gamma isoform X3 [KO:K16342] [EC:]
707592  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:]
707690  PLA2G4F; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:]
100424593  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:]
716098  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
709959  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
710552  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
707310  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
719367  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
698996  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
697523  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X2 [KO:K06276] [EC:]
714717  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
697747  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
700591  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
714645  TSC1; hamartin isoform X1 [KO:K07206]
694965  TSC2; tuberin isoform X7 [KO:K07207]
715378  RHEB; GTP-binding protein Rheb [KO:K07208]
106992736  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
721731  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:]
711979  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:]
703628  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
700538  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta isoform X1 [KO:K00889] [EC:]
710007  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha [KO:K00889] [EC:]
721744  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:]
714474  WAS; wiskott-Aldrich syndrome protein isoform X1 [KO:K05747]
717755  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
696709  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
719305  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
699042  WASF1; wiskott-Aldrich syndrome protein family member 1 isoform X1 [KO:K05753]
716082  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
709849  WASF3; wiskott-Aldrich syndrome protein family member 3 [KO:K06083]
702710  SP1; transcription factor Sp1 [KO:K04684]
721573  PLD2; phospholipase D2 isoform X2 [KO:K01115] [EC:]
694963  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:]
714093  SLC5A7; high affinity choline transporter 1 [KO:K14387]
715816  SLC44A1; choline transporter-like protein 1 isoform X4 [KO:K06515]
715779  SLC44A4; choline transporter-like protein 4 isoform X2 [KO:K15377]
704729  SLC44A5; choline transporter-like protein 5 isoform X1 [KO:K15377]
715866  SLC44A2; choline transporter-like protein 2 isoform X1 [KO:K15377]
714768  SLC44A3; choline transporter-like protein 3 isoform X1 [KO:K15282]
703449  SLC22A1; solute carrier family 22 member 1 isoform X1 [KO:K08198]
708988  SLC22A2; solute carrier family 22 member 2 isoform X1 [KO:K08199]
709454  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
707590  SLC22A5; solute carrier family 22 member 5 isoform X1 [KO:K08202]
710179  SLC22A4; solute carrier family 22 member 4 isoform X1 [KO:K08202]
716377  CHKB; choline/ethanolamine kinase [KO:K14156] [EC:]
710564  CHKA; choline kinase alpha isoform X2 [KO:K14156] [EC:]
704678  HIF1A; hypoxia-inducible factor 1-alpha isoform X4 [KO:K08268]
716452  JUN; transcription factor AP-1 [KO:K04448]
702077  FOS; proto-oncogene c-Fos [KO:K04379]
701760  PCYT1B; choline-phosphate cytidylyltransferase B [KO:K00968] [EC:]
722105  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:]
696056  CHPT1; cholinephosphotransferase 1 isoform X1 [KO:K00994] [EC:]
697069  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:]
721004  PLPP2; phospholipid phosphatase 2 isoform X1 [KO:K01080] [EC:]
715993  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:]
706539  PLPP1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:]
715254  DGKB; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:]
696414  DGKQ; diacylglycerol kinase theta isoform X1 [KO:K00901] [EC:]
710559  DGKA; diacylglycerol kinase alpha isoform X8 [KO:K00901] [EC:]
709578  DGKI; diacylglycerol kinase iota isoform X15 [KO:K00901] [EC:]
714210  DGKD; diacylglycerol kinase delta isoform X4 [KO:K00901] [EC:]
699967  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:]
712450  DGKE; diacylglycerol kinase epsilon isoform X1 [KO:K00901] [EC:]
699337  DGKH; diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:]
713198  DGKZ; diacylglycerol kinase zeta isoform X1 [KO:K00901] [EC:]
695126  DGKK; diacylglycerol kinase kappa isoform X1 [KO:K00901] [EC:]
718412  PRKCA; protein kinase C alpha type [KO:K02677] [EC:]
701195  PRKCB; protein kinase C beta type [KO:K19662] [EC:]
720263  PRKCG; protein kinase C gamma type [KO:K19663] [EC:]
693700  LYPLA1; acyl-protein thioesterase 1 [KO:K06128] [EC:]
721016  acyl-protein thioesterase 1-like [KO:K06128] [EC:]
719117  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 [KO:K18695] [EC:]
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
Glunde K, Bhujwalla ZM, Ronen SM
Choline metabolism in malignant transformation.
Nat Rev Cancer 11:835-48 (2011)
Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO
Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy.
Br J Cancer 102:1-7 (2010)
Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F
Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.
Breast Cancer Res 14:R50 (2012)
Foster DA
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
Biochim Biophys Acta 1791:949-55 (2009)
Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM
Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
Mol Cancer Ther 5:187-96 (2006)
Ridgway ND
The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.
Crit Rev Biochem Mol Biol 48:20-38 (2013)
Awwad HM, Geisel J, Obeid R
The role of choline in prostate cancer.
Clin Biochem 45:1548-53 (2012)
Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D'Ascenzo S, Millimaggi D, Pavan A, Dolo V, Canevari S, Podo F
Alterations of choline phospholipid metabolism in ovarian tumor progression.
Cancer Res 65:9369-76 (2005)
Ackerstaff E, Glunde K, Bhujwalla ZM
Choline phospholipid metabolism: a target in cancer cells?
J Cell Biochem 90:525-33 (2003)
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
Phospholipase signalling networks in cancer.
Nat Rev Cancer 12:782-92 (2012)
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
Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.
Oncogene 29:139-49 (2010)
Glunde K, Jiang L, Moestue SA, Gribbestad IS
MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer.
NMR Biomed 24:673-90 (2011)
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
Nat Chem Biol 5:108-17 (2009)
Foster DA, Xu L
Phospholipase D in cell proliferation and cancer.
Mol Cancer Res 1:789-800 (2003)
Zhou H, Huang S
mTOR signaling in cancer cell motility and tumor metastasis.
Crit Rev Eukaryot Gene Expr 20:1-16 (2010)
mcc00564  Glycerophospholipid metabolism
mcc04010  MAPK signaling pathway
mcc04150  mTOR signaling pathway
mcc04151  PI3K-Akt signaling pathway
mcc04810  Regulation of actin cytoskeleton
KO pathway

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