The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival of prostate cancer cells
Tonelli, Francesca and Alossaimi, Manal and Natarajan, Viswanathan and Gorshkova, Irina and Berdyshev, Evgeny and Bittman, Robert and Watson, David G and Pyne, Susan and Pyne, Nigel J (2013) The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival of prostate cancer cells. Biomolecules, 3 (2). pp. 316-333. ISSN 2218-273X
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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.
Creators(s): |
Tonelli, Francesca, Alossaimi, Manal, Natarajan, Viswanathan, Gorshkova, Irina, Berdyshev, Evgeny, Bittman, Robert, Watson, David G ![]() ![]() ![]() | Item type: | Article |
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ID code: | 49399 |
Keywords: | sphingosine kinase inhibitors, lyso-phosphatidylinositol, sphingolipids, Pharmacy and materia medica, Microbiology |
Subjects: | Medicine > Pharmacy and materia medica Science > Microbiology |
Department: | Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences |
Depositing user: | Pure Administrator |
Date deposited: | 26 Sep 2014 15:48 |
Last modified: | 03 Mar 2021 01:21 |
Related URLs: | |
URI: | https://strathprints.strath.ac.uk/id/eprint/49399 |
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