Abstract
Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.
Highlights
Breast Cancer Cells—We have shown that SKi induces proteasomal degradation of SK1a in MCF-7 cells and this is associated with the onset of apoptosis
Prostate Cancer Cells—We have demonstrated that SKi induces the apoptosis of androgen-sensitive LNCaP prostate cancer cells
Reduced sensitivity to SKi in LNCaP-AI cells might be a matter of titration of SK1b above a threshold level. This possibility is supported by the finding that the sensitivity of SK1b to SKi in terms of proteasomal degradation is enhanced by combined treatment of LNCaP-AI cells with SK1 siRNA and SKi
Summary
Breast Cancer Cells—We have shown that SKi induces proteasomal degradation of SK1a in MCF-7 cells and this is associated with the onset of apoptosis. This possibility is supported by the finding that the sensitivity of SK1b to SKi in terms of proteasomal degradation is enhanced by combined treatment of LNCaP-AI cells with SK1 siRNA and SKi. it should be noted that SKi activates the proteasome to similar extents in LNCaP and LNCaP-AI cells, suggesting that other additional mechanisms might be operative such as modification of SK1b that reduce its sensitivity to SKi-induced proteasomal degradation.
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