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 (S1P2) 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 S1P2 and Y416 phosphorylated c-Src to the nucleus of these cells. This is associated with reduced growth of HA-tagged S1P2 over-expressing MDA-MB-231 cells. Treatment of HA-S1P2 over-expressing MDA-MB-231 cells with the sphingosine 1-phosphate receptor-4 (S1P4) antagonist CYM50367 or with S1P4 siRNA also promoted nuclear translocation of HA-tagged S1P2.

Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1.

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim.

The role of sphingosine 1-phosphate in inflammation and cancer.

The enzymes that catalyze formation of the bioactive sphingolipid, sphingosine 1-phosphate, sphingosine kinase 1 and 2, are predictive markers in inflammatory diseases and cancer as evidenced by data from patients, knockout mice and the use of available molecular and chemical inhibitors. Thus, there is a compelling case for therapeutic targeting of sphingosine kinase. In addition, there are several examples of functional interaction between sphingosine 1-phosphate receptors and sphingosine kinase 1 that can drive malicious amplification loops that promote cancer cell growth.

Sphingosine 1-phosphate receptors and sphingosine kinase 1: novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers.

There is substantial evidence for a role in cancer of the bioactive lipid sphingosine 1-phosphate (S1P), the enzyme sphingosine kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that sphingosine kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome.

Identification of novel functional and spatial associations between sphingosine kinase 1, sphingosine 1-phosphate receptors and other signaling proteins that affect prognostic outcome in estrogen receptor-positive breast cancer.

Sphingosine kinase is an enzyme that catalyses the phosphorylation of sphingosine to form sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane sphingosine 1-phosphate receptors (S1P(1-5) ) and can regulate intracellular target proteins.