title: The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival of prostate cancer cells.
abstract: We have previously shown that treatment of androgen-sensitive LNCaP cells with the sphingosine kinase (SK) inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of two N-terminal variants of SK1 (SK1a and SK1b), increases C22:0-ceramide and diadenosine 5',5'''-P1,P3-triphosphate (Ap3A) and reduces S1P levels, and promotes apoptosis. We have now investigated the effects of three SK inhibitors (SKi, (S)-FTY720 vinylphosphonate, and (R)-FTY720 methyl ether) on metabolite and sphingolipid levels in androgen-sensitive LNCaP and androgen-independent LNCaP-AI prostate cancer cells. The 51 kDa N-terminal variant of SK1 (SK1b) evades the proteasome in LNCaP-AI cells, and these cells do not exhibit an increase in C22:0-ceramide or Ap3A levels and do not undergo apoptosis in response to SKi. In contrast, the SK inhibitor (S)-FTY720 vinylphosphonate induces degradation of SK1b in LNCaP-AI, but not in LNCaP cells. In LNCaP-AI cells, (S)-FTY720 vinylphosphonate induces a small increase in C16:0-ceramide levels and cleavage of polyADPribose polymerase (indicative of apoptosis). Surprisingly, the level of S1P is increased by 7.8- and 12.8-fold in LNCaP and LNCaP-AI cells, respectively, on treatment with (S)-FTY720 vinylphosphonate. Finally, treatment of androgen-sensitive LNCaP cells with the SK2-selective inhibitor (R)-FTY720 methyl ether increases lysophosphatidylinositol levels, suggesting that SK2 may regulate lyso-PI metabolism in prostate cancer cells.
authors: Cell Biology Group and Pharmaceutical Analysis and Metabolomics Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. f.tonelli@dundee.ac.uk.
authors: Francesca
authors: F
authors: Tonelli
authors: Cell Biology Group and Pharmaceutical Analysis and Metabolomics Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. manal.alossaimi@strath.ac.uk.
authors: Manal
authors: M
authors: Alossaimi
authors: University of Illinois at Chicago Department of Pharmacology, 909 S. Wolcott Ave., Chicago, IL 60612, USA. visnatar@uic.edu.
authors: Viswanathan
authors: V
authors: Natarajan
authors: University of Illinois at Chicago, Department of Medicine, 909 S. Wolcott Ave., Chicago, IL 60612, USA. irgorshko@uic.edu.
authors: Irina
authors: I
authors: Gorshkova
authors: University of Illinois at Chicago, Department of Medicine, 909 S. Wolcott Ave., Chicago, IL 60612, USA. eberdysh@uic.edu.
authors: Evgeny
authors: E
authors: Berdyshev
authors: Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367-1597, USA. robert.bittman@qc.cuny.edu.
authors: Robert
authors: R
authors: Bittman
authors: Cell Biology Group and Pharmaceutical Analysis and Metabolomics Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. d.g.watson@strath.ac.uk.
authors: David G
authors: DG
authors: Watson
authors: Cell Biology Group and Pharmaceutical Analysis and Metabolomics Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. susan.pyne@strath.ac.uk.
authors: Susan
authors: S
authors: Pyne
authors: Cell Biology Group and Pharmaceutical Analysis and Metabolomics Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. n.j.pyne@strath.ac.uk.
authors: Nigel J
authors: NJ
authors: Pyne