Anticancer activity of FTY720: Phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D

详细信息    查看全文

• 作者：Laurens A. van Meeteren ; Volker Brinkmann ; Jean Sé ; bastien Saulnier-Blache ; Kevin R. Lynch ; Wouter H. Moolenaar
• 关键词：FTY720 ; Autotaxin ; Lysophosphatidic acid ; Tumor progression
• 刊名：Cancer Letters
• 出版年：2008
• 出版时间：8 August 2008
• 年：2008
• 卷：266
• 期：2
• 页码：203-208
• 全文大小：155 K

文摘

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 0.2 μM) 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 (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.