FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells
Date
2010
Authors
Tonelli, F.
Lim, K.
Loveridge, C.
Long, J.
Pitson, S.
Tigyi, G.
Bittman, R.
Pyne, S.
Pyne, N.
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Journal article
Citation
Cellular Signalling, 2010; 22(10):1536-1542
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Francesca Tonelli, Keng Gat Lim, Carolyn Loveridge, Jaclyn Long, Stuart M. Pitson, Gabor Tigyi, Robert Bittman, Susan Pyne, Nigel J. Pyne
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Abstract
Sphingosine 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.
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Copyright © 2010 Elsevier Inc. All rights reserved.