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.
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.
Tonelli
Francesca
F
Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor St, Glasgow, G4 0NR, UK.
Lim
Keng Gat
KG
Loveridge
Carolyn
C
Long
Jaclyn
J
Pitson
Stuart M
SM
Tigyi
Gabor
G
Bittman
Robert
R
Pyne
Susan
S
Pyne
Nigel J
NJ
D000728:Androgens / Q000502:physiology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014753:Vinyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D000728:Androgens; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D046988:Proteasome Endopeptidase Complex; D013110:Sphingosine; D014753:Vinyl Compounds; D000099157:Sphingosine Kinase; C542743:((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid