Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: The role of sphingosine 1-phosphate receptor-4

We demonstrate that pre-treatment of estrogen receptor negative MDA-MB-231 breast cancer cells containing ectopically expressed HA-tagged sphingosine 1-phosphate receptor-2 (S1P(2)) with the sphingosine kinase 1/2 inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) or the sphingosine kinase 2 selective inhibitor (R)-FTY720 methyl ether (ROMe) or sphingosine kinase 2 siRNA induced the translocation of HA-tagged S1P(2) and Y416 phosphorylated c-Src to the nucleus of these cells. This is associated with reduced growth of HA-tagged S1P(2) over-expressing MDA-MB-231 cells. Treatment of HA-S1P(2) over-expressing MDA-MB-231 cells with the sphingosine I-phosphate receptor-4 (S1P(4)) antagonist CYM50367 or with S1P(4) siRNA also promoted nuclear translocation of HA-tagged S1P(2). These findings identify for the first time a signaling pathway in which sphingosine 1-phosphate formed by sphingosine kinase 2 binds to S1P(4) to prevent nuclear translocation of S1P(2) and thereby promote the growth of estrogen receptor negative breast cancer cells. (C) 2014 Elsevier Inc. All rights reserved.