Journal
CELLULAR SIGNALLING
Volume 23, Issue 10, Pages 1590-1595Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2011.05.010
Keywords
Sphingosine kinase 2; Apoptosis; Kinetics; Breast cancer; FTY720 analogues
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Funding
- Strathclyde University
- NIH [HL083187]
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Sphingosine kinase 2 (SK2) catalyses the conversion of sphingosine to the bioactive lipid sphingosine 1-phosphate (Si P). We report here, the stereospecific synthesis of an analogue of FTY720 called (R)-FTY720-OMe, which we show is a competitive inhibitor of SK2. (R)-FTY720-OMe failed to inhibit sphingosine kinase 1 activity, thereby demonstrating specificity for SK2. Prolonged treatment of HEK 293 cells with (R)-FTY720-OMe also induced a reduction in SK2 expression. In addition. (R)-FTY720-OMe inhibited DNA synthesis and prevented S1P-stimulated rearrangement of actin in MCF-7 breast cancer cells. These findings demonstrate that SK2 functions as a pro-survival protein and is involved in promoting actin rearrangement into membrane ruffles/lamellipodia in response to SIP in MCF-7 breast cancer cells. (C) 2011 Elsevier Inc. All rights reserved.
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