Tonelli, F.Lim, K.Loveridge, C.Long, J.Pitson, S.Tigyi, G.Bittman, R.Pyne, S.Pyne, N.2010-09-282010-09-282010Cellular Signalling, 2010; 22(10):1536-15420898-65681873-3913http://hdl.handle.net/2440/60910Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that FTY720 (Fingolimod) and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 catalytic activity and induce the proteasomal degradation of this enzyme in human pulmonary artery smooth muscle cells, MCF-7 breast cancer cells and androgen-independent LNCaP-AI prostate cancer cells. Proteasomal degradation of SK1 in response to FTY720 and (S)-FTY720 vinylphosphonate is associated with the down-regulation of the androgen receptor in LNCaP-AI cells. (S)-FTY720 vinylphosphonate also induces the apoptosis of these cells. These findings indicate that SK1 is involved in protecting LNCaP-AI from apoptosis. This protection might be mediated by so-called 'inside-out' signalling by S1P, as LNCaP-AI cells exhibit increased expression of S1P(2/3) receptors and reduced lipid phosphate phosphatase expression (compared with androgen-sensitive LNCaP cells) thereby potentially increasing the bioavailability of S1P at S1P(2/3) receptors.enCopyright © 2010 Elsevier Inc. All rights reserved.Sphingosine kinase 1CancerProteasomeFingolimodApoptosisSphingosine 1-phosphate signallingJournal article002009819410.1016/j.cellsig.2010.05.0220002806250000162-s2.0-7795453550233932Pitson, S. [0000-0002-9527-2740]