Ovarian Cancer pp 241-267 | Cite as

Lipid Generation and Signaling in Ovarian Cancer

  • Yan XuEmail author
  • Dongmei Wang
  • Zeneng Wang
Part of the Cancer Treatment and Research book series (CTAR, volume 149)


Remaining as one of the most deadly diseases for the past several decades, ovarian cancer will cause an estimated 15,520 deaths in the United States in 2008.1 From 1991 to 2004, the death rate of ovarian cancer has improved merely 8%.1 Lack of effective early detection, the highly metastatic nature of the disease, and lack of highly effective therapeutic treatment for the late-stage cancer are the main reasons for the low survival rate of patients with ovarian cancer.2, 3, 4

The involvement of extracellular lipid signaling molecules, lysophosphatidic acid (LPA) in particular, in ovarian cancer was first shown in 1995.5,6 Since then, numerous reports have been published demonstrating that LPA regulates almost every aspect of ovarian cancer cell biology, and LPA has been considered as an emerging and important target for ovarian cancer.7, 8, 9, 10, 11, 12, 13, 14, 15Elevated LPA levels in ascites and blood from patients with ovarian cancer have been reported and supported...


Ovarian Cancer Ovarian Cancer Cell Phosphatidic Acid Ovarian Cancer Cell Line Epithelial Ovarian Cancer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to acknowledge Dr. Paul Fox (The Cleveland Clinic Foundation) for letting us use his hypoxia chamber. This work was supported by NIH grants RO1 CA095042 and CA-89228 (to Y.X.).


  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.PubMedGoogle Scholar
  2. 2.
    Bast RC Jr, Brewer M, Zou C, et al. Prevention and early detection of ovarian cancer: mission impossible? Recent Results Cancer Res. 2007;174:91–100.PubMedGoogle Scholar
  3. 3.
    Berchuck A. Biomarkers in the ovary. J Cell Biochem Suppl. 1995;23:223–226.PubMedGoogle Scholar
  4. 4.
    Berchuck A, Elbendary A, Havrilesky L, Rodriguez GC, Bast RC Jr. Pathogenesis of ovarian cancers. J Soc Gynecol Investig. 1994;1(3):181–190.PubMedGoogle Scholar
  5. 5.
    Xu Y, Gaudette DC, Boynton JD, et al. Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res. 1995;1(10):1223–1232.PubMedGoogle Scholar
  6. 6.
    Xu Y, Fang XJ, Casey G, Mills GB. Lysophospholipids activate ovarian and breast cancer cells. Biochem J. 1995;309(Pt 3):933–940.PubMedGoogle Scholar
  7. 7.
    Umezu-Goto M, Tanyi J, Lahad J, et al. Lysophosphatidic acid production and action: validated targets in cancer? J Cell Biochem. 2004;92(6):1115–1140.PubMedGoogle Scholar
  8. 8.
    Sutphen R, Xu Y, Wilbanks GD, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2004;13(7):1185–1191.PubMedGoogle Scholar
  9. 9.
    Xu Y, Xiao YJ, Baudhuin LM, Schwartz BM. The role and clinical applications of bioactive lysolipids in ovarian cancer. J Soc Gynecol Investig. 2001;8(1):1–13.PubMedGoogle Scholar
  10. 10.
    Sengupta S, Wang Z, Tipps R, Xu Y. Biology of LPA in health and disease. Semin Cell Dev Biol. 2004;15(5):503–512.PubMedGoogle Scholar
  11. 11.
    Fang X, Schummer M, Mao M, et al. Lysophosphatidic acid is a bioactive mediator in ovarian cancer. Biochim Biophys Acta. 2002;1582(1–3):257–264.PubMedGoogle Scholar
  12. 12.
    Mills GB, Eder A, Fang X, et al. Critical role of lysophospholipids in the pathophysiology, diagnosis, and management of ovarian cancer. Cancer Treat Res. 2002;107:259–283.PubMedGoogle Scholar
  13. 13.
    Fang X, Gaudette D, Furui T, et al. Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. Ann N Y Acad Sci. 2000;905:188–208.PubMedGoogle Scholar
  14. 14.
    Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer. 2003;3(8):582–591.PubMedGoogle Scholar
  15. 15.
    Xu Y, Sengupta S, Singh S, Steinmetz R. Novel lipid signaling pathways in ovarian cancer cells. Cell Sci Rev. 2006;3:168–197.Google Scholar
  16. 16.
    Xu Y, Shen Z, Wiper DW, et al. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA. 1998;280(8):719–723.PubMedGoogle Scholar
  17. 17.
    Yoon HR, Kim H, Cho SH. Quantitative analysis of acyl-lysophosphatidic acid in plasma using negative ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;788(1):85–92.PubMedGoogle Scholar
  18. 18.
    Sedlakova I, Vavrova J, Tosner J, Hanousek L. Lysophosphatidic acid in ovarian cancer patients. Ceska Gynekol. 2006;71(4):312–317.PubMedGoogle Scholar
  19. 19.
    Umezu-Goto M, Kishi Y, Taira A, et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol. 2002;158(2):227–233.PubMedGoogle Scholar
  20. 20.
    Tokumura A. Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids. Biochim Biophys Acta. 2002;1582(1–3):18–25.PubMedGoogle Scholar
  21. 21.
    Nicosia SV, Bai W, Cheng JQ, Coppola D, Kruk PA. Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am. 2003;17(4):927–943.PubMedGoogle Scholar
  22. 22.
    Kostenis E. Novel clusters of receptors for sphingosine-1-phosphate, sphingosylphosphorylcholine, and (lyso)-phosphatidic acid: new receptors for “old” ligands. J Cell Biochem. 2004;92(5):923–936.PubMedGoogle Scholar
  23. 23.
    Huang MC, Graeler M, Shankar G, Spencer J, Goetzl EJ. Lysophospholipid mediators of immunity and neoplasia. Biochim Biophys Acta. 2002;1582(1–3):161–167.PubMedGoogle Scholar
  24. 24.
    Goetzl EJ, Graeler M, Huang MC, Shankar G. Lysophospholipid growth factors and their G protein-coupled receptors in immunity, coronary artery disease, and cancer. Sci World J. 2002;2:324–338.Google Scholar
  25. 25.
    Contos JJ, Ishii I, Chun J. Lysophosphatidic acid receptors. Mol Pharmacol. 2000;58(6):1188–1196.PubMedGoogle Scholar
  26. 26.
    Budnik LT, Mukhopadhyay AK. Lysophosphatidic acid and its role in reproduction. Biol Reprod. 2002;66(4):859–865.PubMedGoogle Scholar
  27. 27.
    Tigyi G, Parrill AL. Molecular mechanisms of lysophosphatidic acid action. Prog Lipid Res. 2003;42(6):498–526.PubMedGoogle Scholar
  28. 28.
    Aoki J, Taira A, Takanezawa Y, et al. Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem. 2002;277(50):48737–48744.PubMedGoogle Scholar
  29. 29.
    Aoki J. Mechanisms of lysophosphatidic acid production. Semin Cell Dev Biol. 2004;15(5):477–489.PubMedGoogle Scholar
  30. 30.
    Tokumura A, Harada K, Fukuzawa K, Tsukatani H. Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. Biochim Biophys Acta. 1986;875(1):31–38.PubMedGoogle Scholar
  31. 31.
    Tokumura A, Fujimoto H, Yoshimoto O, Nishioka Y, Miyake M, Fukuzawa K. Production of lysophosphatidic acid by lysophospholipase D in incubated plasma of spontaneously hypertensive rats and Wistar Kyoto rats. Life Sci. 1999;65(3):245–253.PubMedGoogle Scholar
  32. 32.
    Imamura F, Horai T, Mukai M, Shinkai K, Sawada M, Akedo H. Induction of in vitro tumor cell invasion of cellular monolayers by lysophosphatidic acid or phospholipase D. Biochem Biophys Res Commun. 1993;193(2):497–503.PubMedGoogle Scholar
  33. 33.
    Moolenaar WH. Lysophospholipids in the limelight: autotaxin takes center stage. J Cell Biol. 2002;158(2):197–199.PubMedGoogle Scholar
  34. 34.
    Tokumura A, Majima E, Kariya Y, et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem. 2002;277(42):39436–39442.PubMedGoogle Scholar
  35. 35.
    van Meeteren LA, Moolenaar WH. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res. 2007;46(2):145–160.PubMedGoogle Scholar
  36. 36.
    Ptaszynska MM, Pendrak ML, Bandle RW, Stracke ML, Roberts DD. Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. Mol Cancer Res. 2008;6(3):352–363.PubMedGoogle Scholar
  37. 37.
    Cui P, Tomsig JL, McCalmont WF, et al. Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors. Bioorg Med Chem Lett. 2007;17(6):1634–1640.PubMedGoogle Scholar
  38. 38.
    Kishi Y, Okudaira S, Tanaka M, et al. Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem. 2006;281(25):17492–17500.PubMedGoogle Scholar
  39. 39.
    Kehlen A, Englert N, Seifert A, et al. Expression, regulation and function of autotaxin in thyroid carcinomas. Int J Cancer. 2004;109(6):833–838.PubMedGoogle Scholar
  40. 40.
    Quinones LG, Garcia-Castro I. Characterization of human melanoma cell lines according to their migratory properties in vitro. In Vitro Cell Dev Biol Anim. 2004;40(1–2):35–42.PubMedGoogle Scholar
  41. 41.
    Desplaces A, Poupon MF. The metastatic process. Bull Cancer. 1994;81(9):751–754.PubMedGoogle Scholar
  42. 42.
    Stracke ML, Krutzsch HC, Unsworth EJ, et al. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem. 1992;267(4):2524–2529.PubMedGoogle Scholar
  43. 43.
    Tokumura A, Kume T, Fukuzawa K, et al. Peritoneal fluids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. Life Sci. 2007;80(18):1641–1649.PubMedGoogle Scholar
  44. 44.
    Clair T, Aoki J, Koh E, et al. Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res. 2003;63(17):5446–5453.PubMedGoogle Scholar
  45. 45.
    Ren J, Xiao YJ, Singh LS, et al. Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res. 2006;66(6):3006–3014.PubMedGoogle Scholar
  46. 46.
    Hu YL, Tee MK, Goetzl EJ, et al. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J Natl Cancer Inst. 2001;93(10):762–768.PubMedGoogle Scholar
  47. 47.
    Tokumura A, Kanaya Y, Miyake M, Yamano S, Irahara M, Fukuzawa K. Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy. Biol Reprod. 2002;67(5):1386–1392.PubMedGoogle Scholar
  48. 48.
    van Meeteren LA, Ruurs P, Christodoulou E, et al. Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J Biol Chem. 2005;280(22):21155–21161.PubMedGoogle Scholar
  49. 49.
    Clair T, Koh E, Ptaszynska M, et al. L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin. Lipids Health Dis. 2005;4(1):5.PubMedGoogle Scholar
  50. 50.
    Chen M, O'Connor KL. Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene. 2005;24(32):5125–5130.PubMedGoogle Scholar
  51. 51.
    Baumforth KR, Flavell JR, Reynolds GM, et al. Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells. Blood. 2005;106(6):2138–2146.PubMedGoogle Scholar
  52. 52.
    Harris AL. Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.PubMedGoogle Scholar
  53. 53.
    Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–684.PubMedGoogle Scholar
  54. 54.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–732.PubMedGoogle Scholar
  55. 55.
    Kim KS, Sengupta S, Berk M, et al. Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo. Cancer Res. 2006;66(16):7983–7990.PubMedGoogle Scholar
  56. 56.
    Xiao Y, Chen Y, Kennedy AW, Belinson J, Xu Y. Evaluation of plasma lysophospholipids for diagnostic significance using electrospray ionization mass spectrometry (ESI-MS) analyses. Ann N Y Acad Sci. 2000;905:242–259.PubMedGoogle Scholar
  57. 57.
    Xiao YJ, Schwartz B, Washington M, et al. Electrospray ionization mass spectrometry analysis of lysophospholipids in human ascitic fluids: comparison of the lysophospholipid contents in malignant vs. nonmalignant ascitic fluids. Anal Biochem. 2001;290(2):302–313.PubMedGoogle Scholar
  58. 58.
    le Balle F, Simon MF, Meijer S, Fourcade O, Chap H. Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid. Adv Enzyme Regul. 1999;39:275–284.PubMedGoogle Scholar
  59. 59.
    Balsinde J, Balboa MA. Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal. 2005;17(9):1052–1062.PubMedGoogle Scholar
  60. 60.
    Balsinde J, Balboa MA, Insel PA, Dennis EA. Regulation and inhibition of phospholipase A2. Annu Rev Pharmacol Toxicol. 1999;39:175–189.PubMedGoogle Scholar
  61. 61.
    Kudo I, Murakami M. Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat. 2002;68–69:3–58.PubMedGoogle Scholar
  62. 62.
    Bonventre JV, Huang Z, Taheri MR, et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature. 1997;390(6660):622–625.PubMedGoogle Scholar
  63. 63.
    Eder AM, Sasagawa T, Mao M, Aoki J, Mills GB. Constitutive and lysophosphatidic acid (LPA)-induced LPA production: role of phospholipase D and phospholipase A2. Clin Cancer Res. 2000;6(6):2482–2491.PubMedGoogle Scholar
  64. 64.
    Cummings BS. Phospholipase A2 as targets for anti-cancer drugs. Biochem Pharmacol. 2007;74(7):949–959.PubMedGoogle Scholar
  65. 65.
    Nakanishi M, Rosenberg DW. Roles of cPLA2alpha and arachidonic acid in cancer. Biochim Biophys Acta. 2006;1761(11):1335–1343.PubMedGoogle Scholar
  66. 66.
    Sengupta S, Xiao YJ, Xu Y. A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells. FASEB J. 2003;17(11):1570–1572.PubMedGoogle Scholar
  67. 67.
    Manguikian AD, Barbour SE. Cell cycle dependence of group VIA calcium-independent phospholipase A2 activity. J Biol Chem. 2004;279(51):52881–52892.PubMedGoogle Scholar
  68. 68.
    Roshak AK, Capper EA, Stevenson C, Eichman C, Marshall LA. Human calcium-independent phospholipase A2 mediates lymphocyte proliferation. J Biol Chem. 2000;275(46):35692–35698.PubMedGoogle Scholar
  69. 69.
    Hazen SL, Gross RW. Human myocardial cytosolic Ca(2+)-independent phospholipase A2 is modulated by ATP. Concordant ATP-induced alterations in enzyme kinetics and mechanism-based inhibition. Biochem J. 1991;280(Pt 3):581–587.PubMedGoogle Scholar
  70. 70.
    Shen Z, Belinson J, Morton RE, Xu Y, Xu Y. Phorbol 12-myristate 13-acetate stimulates lysophosphatidic acid secretion from ovarian and cervical cancer cells but not from breast or leukemia cells. Gynecol Oncol. 1998;71(3):364–368.PubMedGoogle Scholar
  71. 71.
    Zhao X, Wang D, Zhao Z, et al. Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells. J Biol Chem. 2006;281(39):29357–29368.PubMedGoogle Scholar
  72. 72.
    Sengupta S, Kim KS, Berk MP, et al. Lysophosphatidic acid downregulates tissue inhibitor of metalloproteinases, which are negatively involved in lysophosphatidic acid-induced cell invasion. Oncogene. 2007;26(20):2894–2901.PubMedGoogle Scholar
  73. 73.
    Song Y, Wilkins P, Hu W, et al. Inhibition of calcium-independent phospholipase A2 suppresses proliferation and tumorigenicity of ovarian carcinoma cells. Biochem J. 2007;406(3):427–436.PubMedGoogle Scholar
  74. 74.
    Larsson Forsell PK, Runarsson G, Ibrahim M, Bjorkholm M, Claesson HE. On the expression of cytosolic calcium-independent phospholipase A2 (88 kDa) in immature and mature myeloid cells and its role in leukotriene synthesis in human granulocytes. FEBS Lett. 1998;434(3):295–299.PubMedGoogle Scholar
  75. 75.
    Larsson PK, Claesson HE, Kennedy BP. Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity. J Biol Chem. 1998;273(1):207–214.PubMedGoogle Scholar
  76. 76.
    Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, Kudo I. Distinct roles of two intracellular phospholipase A2s in fatty acid release in the cell death pathway. Proteolytic fragment of type IVA cytosolic phospholipase A2alpha inhibits stimulus-induced arachidonate release, whereas that of type VI Ca2+-independent phospholipase A2 augments spontaneous fatty acid release. J Biol Chem. 2000;275(24):18248–18258.PubMedGoogle Scholar
  77. 77.
    Mazurek S, Boschek CB, Eigenbrodt E. The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J Bioenerg Biomembr. 1997;29(4):315–330.PubMedGoogle Scholar
  78. 78.
    Bao S, Miller DJ, Ma Z, et al. Male mice that do not express group VIA phospholipase A2 produce spermatozoa with impaired motility and have greatly reduced fertility. J Biol Chem. 2004;279(37):38194–38200.PubMedGoogle Scholar
  79. 79.
    Burton CA, Patel S, Mundt S, et al. Deficiency in sPLA(2) does not affect HDL levels or atherosclerosis in mice. Biochem Biophys Res Commun. 2002;294(1):88–94.PubMedGoogle Scholar
  80. 80.
    Luquain C, Singh A, Wang L, Natarajan V, Morris AJ. Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells. J Lipid Res. 2003;44(10):1963–1975.PubMedGoogle Scholar
  81. 81.
    Tokumura A, Tsutsumi T, Tsukatani H. Transbilayer movement and metabolic fate of ether-linked phosphatidic acid (1-O-Octadecyl-2-acetyl-sn-glycerol 3-phosphate) in guinea pig peritoneal polymorphonuclear leukocytes. J Biol Chem. 1992;267(11):7275–7283.PubMedGoogle Scholar
  82. 82.
    Kobayashi N, Nishi T, Hirata T, et al. Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J Lipid Res. 2006;47(3):614–621.PubMedGoogle Scholar
  83. 83.
    Amano S, Akutsu N, Ogura Y, Nishiyama T. Increase of laminin 5 synthesis in human keratinocytes by acute wound fluid, inflammatory cytokines and growth factors, and lysophospholipids. Br J Dermatol. 2004;151(5):961–970.PubMedGoogle Scholar
  84. 84.
    Yamada T, Sato K, Komachi M, et al. Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1. J Biol Chem. 2004;279(8):6595–6605.PubMedGoogle Scholar
  85. 85.
    Xu J, Lai YJ, Lin WC, Lin FT. TRIP6 enhances lysophosphatidic acid-induced cell migration by interacting with the lysophosphatidic acid 2 receptor. J Biol Chem. 2004;279(11):10459–10468.PubMedGoogle Scholar
  86. 86.
    Fang X, Yu S, Bast RC, et al. Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem. 2004;279(10):9653–9661.PubMedGoogle Scholar
  87. 87.
    Lee Z, Swaby RF, Liang Y, et al. Lysophosphatidic acid is a major regulator of growth-regulated oncogene alpha in ovarian cancer. Cancer Res. 2006;66(5):2740–2748.PubMedGoogle Scholar
  88. 88.
    Wang P, Wu X, Chen W, Liu J, Wang X. The lysophosphatidic acid (LPA) receptors their expression and significance in epithelial ovarian neoplasms. Gynecol Oncol. 2007;104(3):714–720.PubMedGoogle Scholar
  89. 89.
    Murph M, Tanaka T, Liu S, Mills GB. Of spiders and crabs: the emergence of lysophospholipids and their metabolic pathways as targets for therapy in cancer. Clin Cancer Res. 2006;12(22):6598–6602.PubMedGoogle Scholar
  90. 90.
    Valentine WJ, Fujiwara Y, Tsukahara R, Tigyi G. Lysophospholipid signaling: beyond the EDGs. Biochim Biophys Acta. 2008;1780(3):597–605.PubMedGoogle Scholar
  91. 91.
    Noguchi K, Ishii S, Shimizu T. Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the EDG family. J Biol Chem. 2003;278(28):25600–25606.PubMedGoogle Scholar
  92. 92.
    Yanagida K, Ishii S, Hamano F, Noguchi K, Shimizu T. LPA4/p2y9/GPR23 mediates Rho-dependent morphological changes in a rat neuronal cell line. J Biol Chem. 2007;282(8):5814–5824.PubMedGoogle Scholar
  93. 93.
    Lee CW, Rivera R, Gardell S, Dubin AE, Chun J. GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem. 2006;281(33):23589–23597.PubMedGoogle Scholar
  94. 94.
    Kotarsky K, Boketoft A, Bristulf J, et al. Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J Pharmacol Exp Ther. 2006;318(2):619–628.PubMedGoogle Scholar
  95. 95.
    Pilquil C, Singh I, Zhang QX, et al. Lipid phosphate phosphatase-1 dephosphorylates exogenous lysophosphatidate and thereby attenuates its effects on cell signalling. Prostaglandins Other Lipid Mediat. 2001;64(1–4):83–92.PubMedGoogle Scholar
  96. 96.
    Brindley DN, English D, Pilquil C, Buri K, Ling ZC. Lipid phosphate phosphatases regulate signal transduction through glycerolipids and sphingolipids. Biochim Biophys Acta. 2002;1582(1–3):33–44.PubMedGoogle Scholar
  97. 97.
    Sciorra VA, Morris AJ. Roles for lipid phosphate phosphatases in regulation of cellular signaling. Biochim Biophys Acta. 2002;1582(1–3):45–51.PubMedGoogle Scholar
  98. 98.
    Pyne S, Long JS, Ktistakis NT, Pyne NJ. Lipid phosphate phosphatases and lipid phosphate signalling. Biochem Soc Trans. 2005;33(Pt 6):1370–1374.PubMedGoogle Scholar
  99. 99.
    McDermott MI, Sigal YJ, Crump JS, Morris AJ. Enzymatic analysis of lipid phosphate phosphatases. Methods. 2006;39(2):169–179.PubMedGoogle Scholar
  100. 100.
    Tanyi JL, Hasegawa Y, Lapushin R, et al. Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer. Clin Cancer Res. 2003;9(10 Pt 1):3534–3545.PubMedGoogle Scholar
  101. 101.
    Tanyi JL, Morris AJ, Wolf JK, et al. The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. Cancer Res. 2003;63(5):1073–1082.PubMedGoogle Scholar
  102. 102.
    Imai A, Furui T, Tamaya T, Mills GB. A gonadotropin-releasing hormone-responsive phosphatase hydrolyses lysophosphatidic acid within the plasma membrane of ovarian cancer cells. J Clin Endocrinol Metab. 2000;85(9):3370–3375.PubMedGoogle Scholar
  103. 103.
    Xie Y, Gibbs TC, Mukhin YV, Meier KE. Role for 18:1 lysophosphatidic acid as an autocrine mediator in prostate cancer cells. J Biol Chem. 2002;277(36):32516–32526.PubMedGoogle Scholar
  104. 104.
    Tanaka M, Kishi Y, Takanezawa Y, Kakehi Y, Aoki J, Arai H. Prostatic acid phosphatase degrades lysophosphatidic acid in seminal plasma. FEBS Lett. 2004;571(1–3):197–204.PubMedGoogle Scholar
  105. 105.
    Thompson FJ, Clark MA. Purification of a lysophosphatidic acid-hydrolysing lysophospholipase from rat brain. Biochem J. 1994;300(Pt 2):457–461.PubMedGoogle Scholar
  106. 106.
    West J, Tompkins CK, Balantac N, et al. Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells. DNA Cell Biol. 1997;16(6):691–701.PubMedGoogle Scholar
  107. 107.
    Springett GM, Bonham L, Hummer A, et al. Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies. Cancer Res. 2005;65(20):9415–9425.PubMedGoogle Scholar
  108. 108.
    Panetti TS. Differential effects of sphingosine 1-phosphate and lysophosphatidic acid on endothelial cells. Biochim Biophys Acta. 2002;1582(1–3):190–196.PubMedGoogle Scholar
  109. 109.
    Pyne S, Pyne N. Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol Ther. 2000;88(2):115–131.PubMedGoogle Scholar
  110. 110.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: signaling inside and out. FEBS Lett. 2000;476(1–2):55–57.PubMedGoogle Scholar
  111. 111.
    Wymann MP, Schneiter R. Lipid signalling in disease. Nat Rev Mol Cell Biol. 2008;9(2):162–176.PubMedGoogle Scholar
  112. 112.
    Spiegel S, Kolesnick R. Sphingosine 1-phosphate as a therapeutic agent. Leukemia. 2002;16(9):1596–1602.PubMedGoogle Scholar
  113. 113.
    Yatomi Y. Plasma sphingosine 1-phosphate metabolism and analysis. Biochim Biophys Acta. 2008;1780(3):606–611.PubMedGoogle Scholar
  114. 114.
    Hernandez M, Nieto ML, Sanchez Crespo M. Cytosolic phospholipase A2 and the distinct transcriptional programs of astrocytoma cells. Trends Neurosci. 2000;23(6):259–264.PubMedGoogle Scholar
  115. 115.
    Spiegel S, Milstien S. Exogenous and intracellularly generated sphingosine 1-phosphate can regulate cellular processes by divergent pathways. Biochem Soc Trans. 2003;31(Pt 6):1216–1219.PubMedGoogle Scholar
  116. 116.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4(5):397–407.PubMedGoogle Scholar
  117. 117.
    Yokoo E, Yatomi Y, Takafuta T, Osada M, Okamoto Y, Ozaki Y. Sphingosine 1-phosphate inhibits migration of RBL-2H3 cells via S1P2: cross-talk between platelets and mast cells. J Biochem. 2004;135(6):673–681.PubMedGoogle Scholar
  118. 118.
    Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y. Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol Cell Biol. 2003;23(5):1534–1545.PubMedGoogle Scholar
  119. 119.
    Okamoto H, Takuwa N, Yokomizo T, et al. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol Cell Biol. 2000;20(24):9247–9261.PubMedGoogle Scholar
  120. 120.
    Yamaguchi H, Kitayama J, Takuwa N, et al. Sphingosine-1-phosphate receptor subtype-specific positive and negative regulation of Rac and haematogenous metastasis of melanoma cells. Biochem J. 2003;374(Pt 3):715–722.PubMedGoogle Scholar
  121. 121.
    Lee MJ, Thangada S, Paik JH, et al. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell. 2001;8(3):693–704.PubMedGoogle Scholar
  122. 122.
    Becciolini L, Meacci E, Donati C, Cencetti F, Rapizzi E, Bruni P. Sphingosine 1-phosphate inhibits cell migration in C2C12 myoblasts. Biochim Biophys Acta. 2006;1761(1):43–51.PubMedGoogle Scholar
  123. 123.
    Pyne S, Pyne NJ. Sphingosine 1-phosphate signalling and termination at lipid phosphate receptors. Biochim Biophys Acta. 2002;1582(1–3):121–131.PubMedGoogle Scholar
  124. 124.
    Le Stunff H, Peterson C, Liu H, Milstien S, Spiegel S. Sphingosine-1-phosphate and lipid phosphohydrolases. Biochim Biophys Acta. 2002;1582(1–3):8–17.PubMedGoogle Scholar
  125. 125.
    Brindley DN. Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. J Cell Biochem. 2004;92(5):900–912.PubMedGoogle Scholar
  126. 126.
    Liu H, Chakravarty D, Maceyka M, Milstien S, Spiegel S. Sphingosine kinases: a novel family of lipid kinases. Prog Nucleic Acid Res Mol Biol. 2002;71:493–511.PubMedGoogle Scholar
  127. 127.
    Spiegel S, English D, Milstien S. Sphingosine 1-phosphate signaling: providing cells with a sense of direction. Trends Cell Biol. 2002;12(5):236–242.PubMedGoogle Scholar
  128. 128.
    Mandala SM. Sphingosine-1-phosphate phosphatases. Prostaglandins. 2001;64(1–4):143–156.PubMedGoogle Scholar
  129. 129.
    Olivera A, Spiegel S. Sphingosine kinase: a mediator of vital cellular functions. Prostaglandins Other Lipid Mediat. 2001;64(1–4):123–134.PubMedGoogle Scholar
  130. 130.
    Smicun Y, Reierstad S, Wang FQ, Lee C, Fishman DA. S1P regulation of ovarian carcinoma invasiveness. Gynecol Oncol. 2006;103(3):952–959.PubMedGoogle Scholar
  131. 131.
    Smicun Y, Gil O, Devine K, Fishman DA. S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells. Gynecol Oncol. 2007;107(2):298–309.PubMedGoogle Scholar
  132. 132.
    Park KS, Kim MK, Lee HY, et al. S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochem Biophys Res Commun. 2007;356(1):239–244.PubMedGoogle Scholar
  133. 133.
    Visentin B, Vekich JA, Sibbald BJ, et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell. 2006;9(3):225–238.PubMedGoogle Scholar
  134. 134.
    Murph M, Mills GB. Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert Rev Mol Med. 2007;9(28):1–18.PubMedGoogle Scholar
  135. 135.
    Singh IN, Hall ED. Multifaceted roles of sphingosine-1-phosphate: how does this bioactive sphingolipid fit with acute neurological injury? J Neurosci Res. 2008; May15;86(7):1419–33.Google Scholar
  136. 136.
    Merrill AH Jr, Schmelz EM, Dillehay DL, et al. Sphingolipids – the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol. 1997;142(1):208–225.PubMedGoogle Scholar
  137. 137.
    Hong G, Baudhuin LM, Xu Y. Sphingosine-1-phosphate modulates growth and adhesion of ovarian cancer cells. FEBS Lett. 1999;460(3):513–518.PubMedGoogle Scholar
  138. 138.
    Wang FQ, Smicun Y, Calluzzo N, Fishman DA. Inhibition of matrilysin expression by antisense or RNA interference decreases lysophosphatidic acid-induced epithelial ovarian cancer invasion. Mol Cancer Res. 2006;4(11):831–841.PubMedGoogle Scholar
  139. 139.
    Wang D, Zhao Z, Caperell-Grant A, et al. S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells. Mol Cancer Ther. 2008 July;7(7):1993–2002.Google Scholar
  140. 140.
    Takuwa Y, Takuwa N, Sugimoto N. The EDG family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities. J Biochem (Tokyo). 2002;131(6):767–771.Google Scholar
  141. 141.
    Takuwa Y, Okamoto H, Takuwa N, Gonda K, Sugimoto N, Sakurada S. Subtype-specific, differential activities of the EDG family receptors for sphingosine-1-phosphate, a novel lysophospholipid mediator. Mol Cell Endocrinol. 2001;177(1–2):3–11.PubMedGoogle Scholar
  142. 142.
    Larsson C. Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal. 2006;18(3):276–284.PubMedGoogle Scholar
  143. 143.
    Adams JC. Cell-matrix contact structures. Cell Mol Life Sci. 2001;58(3):371–392.PubMedGoogle Scholar
  144. 144.
    Pawlak G, Helfman DM. Cytoskeletal changes in cell transformation and tumorigenesis. Curr Opin Genet Dev. 2001;11(1):41–47.PubMedGoogle Scholar
  145. 145.
    Pawlak G, Helfman DM. Post-transcriptional down-regulation of ROCKI/Rho-kinase through an MEK-dependent pathway leads to cytoskeleton disruption in Ras-transformed fibroblasts. Mol Biol Cell. 2002;13(1):336–347.PubMedGoogle Scholar
  146. 146.
    Alemany R, van Koppen CJ, Danneberg K, Ter Braak M, Meyer Zu Heringdorf D. Regulation and functional roles of sphingosine kinases. Naunyn Schmiedebergs Arch Pharmacol. 2007;374(5–6):413–428.PubMedGoogle Scholar
  147. 147.
    Spiegel S, Milstien S. Sphingosine 1-phosphate, a key cell signaling molecule. J Biol Chem. 2002;277(29):25851–25854.PubMedGoogle Scholar
  148. 148.
    Moran JM, Buller RM, McHowat J, et al. Genetic and pharmacologic evidence that calcium-independent phospholipase A2beta regulates virus-induced inducible nitric-oxide synthase expression by macrophages. J Biol Chem. 2005;280(30):28162–28168.PubMedGoogle Scholar
  149. 149.
    Meyer AM, Dwyer-Nield LD, Hurteau GJ, et al. Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2. Carcinogenesis. 2004;25(8):1517–1524.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyIndiana UniversityIndianapolisUSA
  2. 2.Department of Cancer BiologyThe Lerner Research Institute, Cleveland ClinicClevelandUSA

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