Objective:BCR/ABL oncoprotein-expression is associated with uncontrolled cell growth. Sphingosine kinase 1(SPK1) regulates the production of sphingosine 1-phosphate(S1P),a key lipid signal molecular in cell proliferation and survival. The objective of this study was to elucidate the roles of S1P and its receptors in bcr/abl positive chronic myeloid leukemia(CML) cells. Methods:The expressions of S1P receptors:S1P1,S1P2 and S1P3 in CML cells were detected by RT-PCR. SPK1 expression,activity and extracellular S1P were determined in ECV304 and HL-60 cells which were transfected with bcr/abl gene. To elucidate the relationship between the BCR/ABL,ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinase),SPK/S1P and S1P/S1P2 signal pathways,bcr/abl positive CML cell line K562 was treated with STI571,PD98059,N,N-dimethyl sphingosine(DMS) and JTE-013. Results:Retrovirus-mediated overexpression of bcr/abl gene in ECV304 and HL-60 cells resulted in upregulation of the expression,activity of SPK1 and increase of the secretion of S1P,whereas treatment of STI571 and PD98059 decreased the BCR/ABL-induced S1P secretion. Treatment of DMS reduced S1P secretion and P42/44MAPK phosphorylation. S1P2-selective antagonist JTE-013 could also decrease P42/44MAPK phosphorylation. Conclusion:These results suggest that BCR/ABL up-regulates extracellular sphingosine 1-phosphate through sphingosine kinase 1 and there is cross-talk between SPK1/S1P/S1P2 and P42/44MAPK in bcr/abl positive CML cells.
