Preferences help
enabled [disable] Abstract
Number of results
2008 | 55 | 2 | 227-240
Article title

Lysophosphatidic acids, cyclic phosphatidic acids and autotaxin as promissing targets in therapies of cancer and other diseases

Title variants
Languages of publication
Lysophospholipids have long been recognized as membrane phospholipid metabolites, but only recently lysophosphatidic acids (LPA) have been demonstrated to act on specific G protein-coupled receptors. The widespread expression of LPA receptors and coupling to several classes of G proteins allow LPA-dependent regulation of numerous processes, such as vascular development, neurogenesis, wound healing, immunity, and cancerogenesis. Lysophosphatidic acids have been found to induce many of the hallmarks of cancer including cellular processes such as proliferation, survival, migration, invasion, and neovascularization. Furthermore, autotaxin (ATX), the main enzyme converting lysophosphatidylcholine into LPA was identified as a tumor cell autocrine motility factor. On the other hand, cyclic phosphatidic acids (naturally occurring analogs of LPA generated by ATX) have anti-proliferative activity and inhibit tumor cell invasion and metastasis. Research achievements of the past decade suggest implementation of preclinical and clinical evaluation of LPA and its analogs, LPA receptors, as well as autotaxin as potential therapeutic targets.
Physical description
  • Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Technical University of Łódź, Łódź, Poland
  • An S, Bleu T, Hallmark OG, Goetzl EJ (1998) Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J Biol Chem 273: 7906-7910.
  • Aoki J (2004) Mechanisms of lysophosphatidic acid production. Semin Cell Dev Biol 15: 477-489.
  • Aoki J, Taira A, Takanezawa Y, Kishi Y, Hama K, Kishimoto T, Mizuno K, Saku K, Taguchi R, Arai H (2002) Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem 277: 48737-48744.
  • Baker DL, Desiderio DM, Miller DD, Tolley B, Tigyi GJ (2001) Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography - mass spectrometry. Anal Biochem 292: 287-295.
  • Baker DL, Fujiwara Y, Pigg KR, Tsukahara R, Kobayashi S, Murofushi H, Uchiyama A, Murakami-Murofushi K, Koh E, Bandle RW, Byun H-S, Bittman R, Fan D, Murph M, Mills GB, Tigyi G (2006) Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. J Biol Chem 281: 22786-22793.
  • Balazs L, Okolicany J, Ferrebee M, Tolley B, Tigyi G (2001) Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo. Am J Physiol Regul Integr Comp Physiol 280: R466-R472.
  • Bandoh K, Aoki J, Hosono H, Kobayashi S, Kobayashi T, Murakami-Murofushi K, Tsujimoto M, Arai H, Inoue K (1999) Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J Biol Chem 274: 27776-27785.
  • Bauer M, Maschberger P, Quek L, Briddon SJ, Dash D, Weiss M, Watson SP, Siess W (2001) Genetic and pharmacological analyses of involvement of Src-family, Syk and Btk tyrosine kinases in platelet shape change: Src-kinases mediate integrin α_Ibβ_3 inside-out signalling during shape change. Thromb Haemost 85: 331-340.
  • Black EJ, Clair T, Delrow J, Neiman P, Gillespie DA (2004) Microarray analysis identifies autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun. Oncogene 23: 2357-2366.
  • Boucharaba A, Serre CM, Guglielmi J, Bordet JC, Clézardin P, Peyruchaud O (2006) The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proc Natl Acad Sci USA 103: 9643-9648.
  • Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, Stracke ML (2003). Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res 63: 5446-5453.
  • Cerutis DR, Dreyer AC, Vierra MJ, King JP, Wagner DJ, Fimple JL, Cordini F, McVaney TP, Parrish LC, Wilwerding TM, Mattson JS (2007) Lysophosphatidic acid modulates the healing responses of human periodontal ligament fibroblasts and enhances the actions of platelet-derived growth factor. J Periodontol 78: 1136-1145.
  • Chen M, O'Connor KL (2005) Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene 24: 5125-5130.
  • Chen X, Yang XY, Wang ND, Ding C, Yang YJ, You ZJ, Su Q, Chen JH (2003) Serum lysophosphatidic acid concentrations measured by dot immunogold filtration assay in patients with acute myocardial infarction. Scand J Clin Lab Invest 63: 497-503.
  • Contos JJ, Ishii I, Chun J (2000) Lysophosphatidic acid receptors. Mol Pharmacol 58: 1188-1196.
  • Cui P, Tomsig JL, McCalmont WF, Lee S, Becker CJ, Lynch KR, Macdonald TL (2007) Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors. Bioorg Med Chem Lett 17: 1634-1640.
  • Dever G, Wainwright CL, Kennedy S, Spickett CM (2006) Fatty acid and phospholipid chlorohydrins cause cell stress and endothelial adhesion. Acta Biochim Polon 53: 761-768.
  • Eichholtz T, Jalink K, Fahrenfort I, Moolenaar WH (1993) The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J 291: 677-680.
  • English D, Cui Y, Siddiqui R, Patterson C, Natarajan V, Brindley DN, Garcia JG (1999) Induction of endothelial monolayer permeability by phosphatidate. J Cell Biochem 75: 105-117.
  • Fang X, Gaudette D, Furui T, Mao M, Estrella V, Eder A, Pustilnik T, Sasagawa A, Lapushin R, Yu S, Jaffe RB, Wiener JR, Erickson JR, Mills GB (2000) Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. Ann N Y Acad Sci 905: 188-208.
  • Fang X, Yu S, Bast RC, Liu S, Xu HJ, Hu SX, LaPushin R, Claret FX, Aggarwal BB, Lu Y, Mills GB (2004) Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem 279: 9653-9661.
  • Fourcade O, Simon MF, Viode C, Rugani N, Leballe F, Ragab A, Fournie B, Sarda L, Chap H (1995) Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 80: 919-927.
  • Gardell SE, Dubin AE, Chun J (2006) Emerging medicinal roles for lysophospholipid signaling. Trends Mol Med 12: 65-75.
  • Hao F, Tan M, Xu X, Han J, Miller DD, Tigyi G, Cui MZ (2007) Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA_1, p42 and p38α. Biochim Biophys Acta 1771: 883-892.
  • Hecht JH, Weiner JA, Post SR, Chun J (1996) Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J Cell Biol 135: 1071-1083.
  • Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001) Lysophospholipids - receptor revelations. Science 294: 1875-1878.
  • Hu YL, Tee MK, Goetzl EJ, Auersperg N, Mills GB, Ferrara N, Jaffe RB (2001) Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J Natl Cancer Inst 93: 762-768.
  • Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H. (2004) Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10: 712-718.
  • Ishihara R, Tatsuta M, Iishi H, Baba M, Uedo N, Higashino K, Mukai M, Ishiguro S, Kobayashi S, Murakami-Murofushi (2004) Attenuation by cyclic phosphatidic acid of peritoneal metastasis of azoxymethane-induced intestinal cancers in Wistar rats. Int J Cancer 110: 188-193.
  • Jansen S, Stefan C, Creemers JWM, Waelkens E, van Eynde A, Stalmans W, Bollen M (2005) Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. J Cell Sci 118: 3081-3089.
  • Jansen S, Callewaert N, Dewerte I, Andries M, Ceulemans H, Bollen M (2007) An essential oligomannosidic glycan chain in the catalytic domain of autotaxin, a secreted lysophospholipase-D. J Biol Chem 282: 11084-11091.
  • Kang YC, Kim KM, Lee, Namkoong S, Lee SJ, Han JA, Jeoung D, Ha^ KS, Kwon YG, Kim M (2004) Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation. Cell Death Differ 11: 1287-1298.
  • Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J (2003) Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci 6: 1292-1299.
  • Kishi Y, Okudaira S, Tanaka M, Hama K, Shida D, Kitayama J, Yamori T, Aoki J, Fujimaki T, Arai H (2006) Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem 281: 17492-17500.
  • Kobayashi T, Tanaka-Ishii R, Taguchi R, Ikezawa H, Murakami-Murofushi K (1999) Existence of a bioactive lipid, cyclic phosphatidic acid, bound to human serum albumin. Life Sci 65: 2185-2191.
  • Kotarsky K, Boketoft A, Bristulf J, Nilsson NE, Norberg A, Hansson S, Owman C, Sillard R, Leeb-Lundberg LMF Olde B (2006) Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J Pharmacol Exp Ther 318: 619-628.
  • Lee CH, Olson P, Evans RM (2003a) Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144: 2201-2207.
  • Lee CW, Rivera R, Gardell S, Dubin AE, Chun J (2006a) GPR92 as a new G_12/13 and G_q coupled lysophosphatidic acid receptor that increases cAMP: LPA_5. J Biol Chem 281: 23589-23597.
  • Lee DJ, Ho C-H, Grinnell F (2003b) LPA-stimulated fibroblast contraction of floating collagen matrices does not require Rho kinase activity or retraction of fibroblast extensions. Exp Cell Res 289: 86-94.
  • Lee H, Geotzl EJ, An S (2000) Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing. Am J Physiol Cell Physiol 278: C612-C617.
  • Lee J, Park SY, Lee EK, Park CG, Chung HC, Rha SY, Kim YK, Bae GU, Kim BK, Han JW, Lee HY (2006b) Activation of hypoxia-inducible factor-1{alpha} is necessary for lysophosphatidic acid-induced vascular endothelial growth factor expression. Clin Cancer Res 12: 6351-6358.
  • Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270: 12953-12956.
  • Li H, Ye X, Mahanivong C, Bian D, Chun J, Huang S (2005) Signaling mechanisms responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. J Biol Chem 280: 10564-10571.
  • Lin CI, Chen CN, Lin PW, Chang KJ, Hsieh FJ, Lee H (2007) Lysophosphatidic acid regulates inflammation-related genes in human endothelial cells through LPA_1 and LPA_3._ Biochem Biophys Res Commun 363: 1001-1008.
  • McIntyre TM, Pontsler AV, Silva AR, Hilaire AS, Xu Y, Hinshaw JC, Zimmerman GA, Hama K, Aoki J, Arai H, Prestwich GD (2003) Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist. Proc Natl Acad Sci USA 100: 131-136.
  • Meyer zu Heringdorf D, Jacobs KH (2007) Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta 1768: 923-940.
  • Mills GB, Moolenaar WH (2003) The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3: 582-591.
  • Mukai M, Nakamura H, Tatsuta M, Iwasaki T, Togawa A, Imamura F, Akedo H (2000) Hepatoma cell migration through a mesothelial cell monolayer is inhibited by cyclic AMP-elevating agents via a Rho-dependent pathway. FEBS Lett 484: 69-73.
  • Murakami-Murofushi K, Shioda M, Kaji K, Yoshida S, Murofushi H (1992) Inhibition of eukaryotic DNA polymerase alpha with a novel lysophosphatidic acid (PHYLPA) isolated from myxoamoebae of Physarum polycephalum. J Biol Chem. 267: 21512-21517.
  • Murakami-Murofushi K, Kaji K, Kano K, Fukuda M, Shioda M, Murofushi H (1993) Inhibition of cell proliferation by a unique lysophosphatidic acid, PHYLPA, isolated from Physarum polycephalum: signaling events of antiproliferative action by PHYLPA. Cell Struct Funct 18: 363-370.
  • Nakamura K, Igarashi K, Ide K, Ohkawa R, Okubo S, Yokota H, Masuda A, Oshima N, Takeuchi T, Nangaku M, Okudaira S, Arai H, Ikeda H, Aoki J, Yatomi Y (2008) Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation. Clin Chim Acta 388: 51-58.
  • Noguchi K, Ishii S, Shimizu T (2003) Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J Biol Chem 278: 25600-25606.
  • Pilquil C, Dewald J, Cherney A, Gorshkova I, Tigyi G, English D, Natarajan V, Brindley DN (2006) Lipid phosphate phosphatase-1 regulates lysophosphatidate-induced fibroblast migration by controlling phospholipase D_2-dependent phosphatidate generation. J Biol Chem 281: 38418-38429.
  • Pyne S, Kong K-C, Darroch PI (2004) Lysophosphatidic acid and sphingosine 1-phosphate biology: the role of lipid phosphate phosphatases. Semin Cell Dev Biol 15: 491-501.
  • Retzer M, Essler M (2000) Lysophosphatidic acid-induced platelet shape change proceeds via Rho/Rho kinase-mediated myosin light-chain and moesin phosphorylation. Cell Signal 12: 645-648.
  • Rother E, Brandl R, Baker DL, Goyal P, Gebhard H, Tigyi G, Siess W (2003) Subtype-selective antagonists of lysophosphatidic acid receptors inhibit platelet activation triggered by the lipid core of atherosclerotic plaques. Circulation 108: 741-747.
  • Sano T, Baker D, Virag T, Wada A, Yatomi Y, Kobayashi T, Igarashi Y, Tigyi G (2002) Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. J Biol Chem 277: 21197-21206.
  • Siess W (2002) Athero- and thrombogenic actions of lysophosphatidic acid and sphingosine-1-phosphate. Biochim Biophys Acta 1582: 204-215.
  • Siess W, Zangl KJ, Essler M, Bauer M, Brandl R, Corrinth C, Bittman R, Tigyi G, Aepfelbacher M (1999) Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. Proc Natl Acad Sci USA 96: 6931-6936.
  • Simon MF, Rey A, Castan-Laurel I, Gres S, Sibrac D, Valet P, Saulnier-Blache JS (2002) Expression of ectolipid phosphate phosphohydrolases in 3T3F442A preadipocytes and adipocytes. Involvement in the control of lysophosphatidic acid production. J Biol Chem 277: 23131-23136.
  • Simon MF, Daviaud D, Pradere JP, Gres S, Guigne C, Wabitsch M, Chun J, Valet P, Saulnier-Blache JS (2005) Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2. J Biol Chem 280: 14656-14662.
  • So J, Navari J, Wang FQ, Fishman DA (2004) Lysophosphatidic acid enhances epithelial ovarian carcinoma invasion through the increased expression of interleukin-8. Gynecol Oncol 95: 314-322.
  • Stefan C, Jansen S, Bollen M (2005) NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci 30: 542-550.
  • Sturm A, Dignass AU (2002) Modulation of gastrointestinal wound repair and inflammation by phospholipids. Biochim Biophys Acta 1582: 282-288.
  • Sugiura T, Nakane S, Kishimoto S, Waku K, Yoshioka Y, Tokumura A (2002) Lysophosphatidic acid, a growth factor-like lipid, in the saliva. J Lipid Res 43: 2049-2055.
  • Tigyi G, Parrill AL (2003) Molecular mechanisms of lysophosphatidic acid action. Prog Lipid Res 42: 498-526.
  • Tanaka M, Okudaira S, Kishi Y, Ohkawa R, Iseki S, Ota M, Noji S, Yatomi Y, Aoki J, Arai H (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem 281: 25822-25830.
  • Toews ML, Ediger TL, Romberger DJ, Rennard SI (2002) Lysophosphatidic acid in airway function and disease. Biochim Biophys Acta 1582: 240-250.
  • Tokumura A, Fukuzawa K, Tsukatani H (1978) Effects of synthetic and natural lysophosphatidic acids on the arterial blood pressure of different animal species. Lipids 13: 572-574.
  • Tokumura A, Harada K, Fukuzawa K, Tsukanani H (1986) Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. Biochim Biophys Acta 875: 31-38.
  • Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277: 39436-39442.
  • Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, Aoki J, Arai H, Murakami-Murofushi K, Kobayashi T (2006) Cyclic phosphatidic acid is produced by autotaxin in blood. J Biol Chem 281: 26081-26088.
  • Uchiyama A, Mukai M, Fujiwara Y, Kobayashi S, Kawai N, Murofushi H, Inoue M, Enoki S, Tanaka Y, Niki T, Kobayashi T, Tigyi G, Murakami-Murofushi K (2007) Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid. Biochim Biophys Acta 1771: 103-112.
  • Ueda H (2006) Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 109: 57-77.
  • Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158: 227-233.
  • van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH (1989) Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 59: 45-54.
  • van Meeteren LA, Ruurs P, Christodoulou E, Goding JW, Takakusa H, Kikuchi K, Perrakis A, Nagano T, Moolenaar W (2005) Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J Biol Chem 280: 21155-21161.
  • van Meeteren LA, Moolenaar WH (2007) Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 46: 145-160.
  • Wang P, Wu X, Chen W, Liu J, Wang X (2007) The lysophosphatidic acid (LPA) receptors their expression and significance in epithelial ovarian neoplasms. Gynecol Oncol 104: 714-720.
  • Watterson KR, Lanning DA, Diegelmann RF, Spiegel S (2007) Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen 15: 607-616.
  • Wójcik M, Cieślak M, Stec WJ, Goding JW, Koziolkiewicz M (2007) Nucleotide pyrophosphatase/phosphodiesterase 1 is responsible for degradation of antisense phosphorothioate oligonucleotides. Oligonucleotides 17: 134-145.
  • Wu WT, Chen C-N, Lin CI, Chen JH, Lee H (2005) Lysophospholipids enhance matrix metalloproteinase-2 expression in human endothelial cells. Endocrinology 146: 3387-3400.
  • Yoshida K, Nishida W, Hayashi K, Ohkawa Y, Ogawa A, Aoki J, Arai H, Sobue K (2003) Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo. Circulation 108: 1746-1752.
  • Zhang C, Baker DL, Yasuda S, Makarova N, Balans L, Johnson LR, Marathe GK, McIntyre TM, Xu Y, Prestwich GD, Byun H-S, Bittman R, Tigyi G (2004) Lysophosphatidic acid induces neointima formation through PPARγ activation. J Exp Med 199: 763-774.
  • Zhang Z, Liu Z, Meier KE (2006) Lysophosphatidic acid as a mediator for proinflammatory agonists in a human corneal epithelial cell line. Am J Physiol Cell Physiol 291: C1089-C1098.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.