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.

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.

• Authors: Francesca Tonelli, Keng Gat Lim, Carolyn Loveridge, Jaclyn Long, Stuart M Pitson, Gabor Tigyi, Robert Bittman, Susan Pyne, Nigel J Pyne
• Journal: Cellular signalling (Cell Signal) Vol. 22 Issue 10 Pg. 1536-42 (Oct 2010) ISSN: 1873-3913 [Electronic] England
• PMID: 20570726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• ((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid
• Androgens
• Antineoplastic Agents
• Enzyme Inhibitors
• Organophosphonates
• Propylene Glycols
• Vinyl Compounds
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Proteasome Endopeptidase Complex
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Androgens (physiology)
• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (enzymology)
• Cell Line, Tumor
• Cells, Cultured
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (chemistry, pharmacology)
• Female
• Fingolimod Hydrochloride
• Humans
• Male
• Muscle, Smooth, Vascular (drug effects, enzymology)
• Organophosphonates
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, metabolism)
• Propylene Glycols (chemistry, pharmacology)
• Prostatic Neoplasms (enzymology)
• Proteasome Endopeptidase Complex (metabolism)
• Pulmonary Artery (cytology)
• Sphingosine (analogs & derivatives, chemistry, pharmacology)
• Stereoisomerism
• Vinyl Compounds (chemistry, pharmacology)