title: (R)-FTY720 methyl ether is a specific sphingosine kinase 2 inhibitor: Effect on sphingosine kinase 2 expression in HEK 293 cells and actin rearrangement and survival of MCF-7 breast cancer cells.
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.
authors.affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK.
authors.forename: Keng Gat
authors.initials: KG
authors.lastname: Lim
authors.forename: Chaode
authors.initials: C
authors.lastname: Sun
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D057075:Enzyme Assays / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011409:Propylene Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D011554:Pseudopodia / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate