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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Tonelli, F. and Lim, K.G. and Loveridge, Carolyn and Long, J. and Pitson, S.M. and Tigyi, G. and Bittman, R. and Pyne, S. and Pyne, N.J. (2010) 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. Cellular Signalling, 22 (10). pp. 1536-1542. ISSN 1873-3913 (https://doi.org/10.1016/j.cellsig.2010.05.022)

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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.

ORCID iDs

Tonelli, F., Lim, K.G., Loveridge, Carolyn, Long, J., Pitson, S.M., Tigyi, G., Bittman, R., Pyne, S. ORCID logoORCID: https://orcid.org/0000-0002-6608-9584 and Pyne, N.J. ORCID logoORCID: https://orcid.org/0000-0002-5657-4578;
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