Journal
CANCER LETTERS
Volume 266, Issue 2, Pages 203-208Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2008.02.052
Keywords
FTY720; autotaxin; lysophosphatidic acid; tumor progression
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Funding
- NIGMS NIH HHS [R01 GM067958, R01 GM067958-06] Funding Source: Medline
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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 (K(i)similar to 0.2 PM) 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 NPPl, the closest relative of ATX, After oral administration in mice, FTY720 (3 mg/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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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