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2013 ; 3
(2
): 316-33
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The roles of sphingosine kinase 1 and 2 in regulating the metabolome and survival
of prostate cancer cells
#MMPMID24970170
Tonelli F
; Alossaimi M
; Natarajan V
; Gorshkova I
; Berdyshev E
; Bittman R
; Watson DG
; Pyne S
; Pyne NJ
Biomolecules
2013[Jun]; 3
(2
): 316-33
PMID24970170
show ga
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.