Anticancer activity of FTY720: phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D.
FTY720 is an immunomodulator that is phosphorylated in vivo and inhibits lymphocyte mobilization by targeting sphingosine 1-phospate receptors. At doses higher than required for immunomodulation, FTY720 inhibits tumor progression through an unknown mechanism. Here we show that FTY720-phosphate is a competitive inhibitor (Ki approximately 0.2microM) of autotaxin (ATX or NPP2), a nucleotide phosphodiesterase/pyrophosphatase (NPP) that enhances metastasis and angiogenesis and acts as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA). FTY720-phosphate did no affect the activity of NPP1, the closest relative of ATX. After oral administration in mice, FTY720 (3mg/kg) significantly reduced plasma LPA levels. These results suggest that FTY720 may exert its anticancer effects, at least in part, by targeting the ATX-LPA axis.
van Meeteren
Laurens A
LA
Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 Amsterdam, The Netherlands.
Brinkmann
Volker
V
Saulnier-Blache
Jean Sébastien
JS
Lynch
Kevin R
KR
Moolenaar
Wouter H
WH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000099189:Lysophospholipase D
D000970:Antineoplastic Agents; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D010755:Organophosphates; D043264:Phosphodiesterase I; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D013110:Sphingosine; D000099189:Lysophospholipase D; C525008:FTY 720P; C032881:lysophosphatidic acid