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

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dc.contributor.authorTonelli, F.
dc.contributor.authorLim, K.
dc.contributor.authorLoveridge, C.
dc.contributor.authorLong, J.
dc.contributor.authorPitson, S.
dc.contributor.authorTigyi, G.
dc.contributor.authorBittman, R.
dc.contributor.authorPyne, S.
dc.contributor.authorPyne, N.
dc.date.issued2010
dc.description.abstractSphingosine 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.
dc.description.statementofresponsibilityFrancesca Tonelli, Keng Gat Lim, Carolyn Loveridge, Jaclyn Long, Stuart M. Pitson, Gabor Tigyi, Robert Bittman, Susan Pyne, Nigel J. Pyne
dc.identifier.citationCellular Signalling, 2010; 22(10):1536-1542
dc.identifier.doi10.1016/j.cellsig.2010.05.022
dc.identifier.issn0898-6568
dc.identifier.issn1873-3913
dc.identifier.orcidPitson, S. [0000-0002-9527-2740]
dc.identifier.urihttp://hdl.handle.net/2440/60910
dc.language.isoen
dc.publisherElsevier Science Inc
dc.rightsCopyright © 2010 Elsevier Inc. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.cellsig.2010.05.022
dc.subjectSphingosine kinase 1
dc.subjectCancer
dc.subjectProteasome
dc.subjectFingolimod
dc.subjectApoptosis
dc.subjectSphingosine 1-phosphate signalling
dc.titleFTY720 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
dc.typeJournal article
pubs.publication-statusPublished

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