Abstract
Sphingosine kinase 2 (SK2) catalyses the conversion of sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). 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 S1P in MCF-7 breast cancer cells.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / drug effects
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Actins / metabolism*
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Antineoplastic Agents / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Cell Membrane / metabolism
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Enzyme Assays / methods
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Female
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Fingolimod Hydrochloride
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HEK293 Cells
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Humans
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Lysophospholipids / metabolism
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Microscopy, Fluorescence
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Propylene Glycols / chemical synthesis
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Propylene Glycols / pharmacology*
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Pseudopodia / metabolism
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Sphingosine / analogs & derivatives*
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Sphingosine / chemical synthesis
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Sphingosine / metabolism
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Sphingosine / pharmacology
Substances
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Actins
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Antineoplastic Agents
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Lysophospholipids
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Propylene Glycols
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sphingosine 1-phosphate
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Fingolimod Hydrochloride
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Sphingosine