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https://hdl.handle.net/2440/60910
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Type: | Journal article |
Title: | 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 |
Author: | Tonelli, F. Lim, K. Loveridge, C. Long, J. Pitson, S. Tigyi, G. Bittman, R. Pyne, S. Pyne, N. |
Citation: | Cellular Signalling, 2010; 22(10):1536-1542 |
Publisher: | Elsevier Science Inc |
Issue Date: | 2010 |
ISSN: | 0898-6568 1873-3913 |
Statement of Responsibility: | Francesca Tonelli, Keng Gat Lim, Carolyn Loveridge, Jaclyn Long, Stuart M. Pitson, Gabor Tigyi, Robert Bittman, Susan Pyne, Nigel J. Pyne |
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. |
Keywords: | Sphingosine kinase 1 Cancer Proteasome Fingolimod Apoptosis Sphingosine 1-phosphate signalling |
Rights: | Copyright © 2010 Elsevier Inc. All rights reserved. |
DOI: | 10.1016/j.cellsig.2010.05.022 |
Published version: | http://dx.doi.org/10.1016/j.cellsig.2010.05.022 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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