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

Francesca Tonelli, Keng Gat Lim, Carolyn Loveridge, Jaclyn Long, Stuart M. Pitson, Gabor Tigyi, Robert Bittman, Susan Pyne, Nigel J. Pyne

Research output: Contribution to journalArticle

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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 S1P2/3 receptors and reduced lipid phosphate phosphatase expression (compared with androgen-sensitive LNCaP cells) thereby potentially increasing the bioavailability of S1P at S1P2/3 receptors.

Original languageEnglish (US)
Pages (from-to)1536-1542
Number of pages7
JournalCellular Signalling
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2010

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Muscle Neoplasms
Pulmonary Artery
Androgens
Smooth Muscle
Prostatic Neoplasms
Breast Neoplasms
Lysosphingolipid Receptors
Apoptosis
Sphingosine
Androgen Receptors
Enzymes
Biological Availability
Smooth Muscle Myocytes
((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid
Fingolimod Hydrochloride
sphingosine kinase
Down-Regulation
Phosphorylation
Lipids

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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. / Tonelli, Francesca; Lim, Keng Gat; Loveridge, Carolyn; Long, Jaclyn; Pitson, Stuart M.; Tigyi, Gabor; Bittman, Robert; Pyne, Susan; Pyne, Nigel J.

In: Cellular Signalling, Vol. 22, No. 10, 01.10.2010, p. 1536-1542.

Research output: Contribution to journalArticle

Tonelli, Francesca ; Lim, Keng Gat ; Loveridge, Carolyn ; Long, Jaclyn ; Pitson, Stuart M. ; Tigyi, Gabor ; Bittman, Robert ; Pyne, Susan ; Pyne, Nigel J. / 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. In: Cellular Signalling. 2010 ; Vol. 22, No. 10. pp. 1536-1542.
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