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.
Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA. ysekine@showa.gunma-u.ac.jp
Yoshitaka
Y
Sekine
Kazuhiro
K
Suzuki
Alan T
AT
Remaley
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D008076:Cholesterol, HDL / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D008076:Cholesterol, HDL; D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C060506:sphingosine 1-phosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013110:Sphingosine