HDL and Sphingosine-1-Phosphate Activate Stat3 in Prostate Cancer DU145 Cells Via ERK1/2 and S1P Receptors, and Promote Cell Migration and Invasion

BACKGROUND. Androgen deprivation therapy in men with prostate cancer leads to a significant increase of high density lipoprotein (HDL), but the effect of HDL on prostate cancer is unknown. Recently, HDL, which transports sphingosine-1-phosphate (S1P), was reported to activate signal transducer and activator of transcription 3 (Stat3) in cardiomyocytes. In this study, we examined the effect of HDL and S1P on Stat3 activation in prostate cancer cells and the involvement of S1P receptors in this process in three prostate cancer cell lines (PC-3, LNCaP, and DU145). METHODS. Discordial reconstituted(r) HDL containing POPC, apoA-1, and S1P were prepared by the cholate dialysis method. The phosphorylations of Stat3, ERK1/2, and Akt were detected by Western blotting. Cell migration and invasion were determined by wound-healing assay and matrigel invasion chamber assay. RESULTS. HDL increased serine 727 phosphorylation of Stat3, but not tyrosine 705 only in DU145 cells. S1P and rHDL-S1P also induced the phosphorylation, but not rHDL without S1P. They also induced DU145 cells migration and invasion. PD98059, a MEK inhibitor, and pertussis toxin, a Gi inhibitor, attenuated HDL-, S1P-, and rHDL-S1P-induced Stat3 phosphorylation, whereas LY294002, a PI3K inhibitor, had no effect. Concerning S1P receptors, S1P1 expression was much lower than S1P2 and S1P3 in DU145 cells. Both JTE013, a S1P2 antagonist, and VPC23019, a S1P1/S1P3 antagonist, attenuated HDL-, S1P-, and rHDL-S1P-induced Stat3 phosphorylations and cell migrations. CONCLUSIONS. These results suggest that the change in HDL plasma levels by androgen deprivation therapy may alter prostate cancer growth and metastasis. Prostate 71: 690-699, 2011. (C) 2010 Wiley-Liss, Inc.