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The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells
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
University of Illinois at Chicago Department of Pharmacology, 909 S. Wolcott Ave., Chicago, IL 60612, USA
University of Illinois at Chicago, Department of Medicine, 909 S. Wolcott Ave., Chicago, IL 60612, USA
Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367-1597, USA
* Author to whom correspondence should be addressed.
Received: 9 May 2013; in revised form: 3 June 2013 / Accepted: 4 June 2013 / Published: 10 June 2013
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.
Keywords: Sphingosine kinase inhibitors; lyso-phosphatidylinositol; sphingolipids; diadenosine 5′,5′′′-P1,P3-triphosphate
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Tonelli, F.; Alossaimi, M.; Natarajan, V.; Gorshkova, I.; Berdyshev, E.; Bittman, R.; Watson, D.G.; Pyne, S.; Pyne, N.J. The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells. Biomolecules 2013, 3, 316-333.
Tonelli F, Alossaimi M, Natarajan V, Gorshkova I, Berdyshev E, Bittman R, Watson DG, Pyne S, Pyne NJ. The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells. Biomolecules. 2013; 3(2):316-333.
Tonelli, Francesca; Alossaimi, Manal; Natarajan, Viswanathan; Gorshkova, Irina; Berdyshev, Evgeny; Bittman, Robert; Watson, David G.; Pyne, Susan; Pyne, Nigel J. 2013. "The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells." Biomolecules 3, no. 2: 316-333.