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.