The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival of prostate cancer cells

Francesca Tonelli, Manal Alossaimi, Viswanathan Natarajan, Irina Gorshkova, Evgeny Berdyshev, Robert Bittman, David G Watson, Susan Pyne, Nigel J Pyne

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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.

Original languageEnglish
Pages (from-to)316-333
Number of pages18
JournalBiomolecules
Volume3
Issue number2
Early online date10 Jun 2013
DOIs
Publication statusPublished - 2013

Keywords

  • sphingosine kinase inhibitors
  • lyso-phosphatidylinositol
  • sphingolipids

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    Tonelli, F., Alossaimi, M., Natarajan, V., Gorshkova, I., Berdyshev, E., Bittman, R., Watson, D. G., Pyne, S., & Pyne, N. J. (2013). The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival of prostate cancer cells. Biomolecules, 3(2), 316-333. https://doi.org/10.3390/biom3020316