FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells

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• 作者：Francesca Tonelli ; Keng Gat Lim ; Carolyn Loveridge ; Jaclyn Long ; Stuart M. Pitson ; Gabor Tigyi ; Robert Bittman ; Susan Pyne ; Nigel J. Pyne
• 关键词：Sphingosine kinase 1 ; Cancer ; Proteasome ; Fingolimod ; Apoptosis ; Sphingosine 1-phosphate signalling
• 刊名：Cellular Signalling
• 出版年：2010
• 出版时间：October 2010
• 年：2010
• 卷：22
• 期：10
• 页码：1536-1542
• 全文大小：443 K

文摘

Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that FTY720 (Fingolimod™) and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 catalytic activity and induce the proteasomal degradation of this enzyme in human pulmonary artery smooth muscle cells, MCF-7 breast cancer cells and androgen-independent LNCaP-AI prostate cancer cells. Proteasomal degradation of SK1 in response to FTY720 and (S)-FTY720 vinylphosphonate is associated with the down-regulation of the androgen receptor in LNCaP-AI cells. (S)-FTY720 vinylphosphonate also induces the apoptosis of these cells. These findings indicate that SK1 is involved in protecting LNCaP-AI from apoptosis. This protection might be mediated by so-called ‘inside-out’ signalling by S1P, as LNCaP-AI cells exhibit increased expression of S1P_2/3 receptors and reduced lipid phosphate phosphatase expression (compared with androgen-sensitive LNCaP cells) thereby potentially increasing the bioavailability of S1P at S1P_2/3 receptors.