Abstract 5107: HDL and sphingosine-1-phosphate activate signal transducer and activator of transcription 3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 8_Supplement; p. 5107
• Main Authors: Sekine, Yoshitaka, Suzuki, Kazuhiro, Remaley, Alan T.
• Format: Journal Article
• Language: English
• Published: 15.04.2010
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-5107

Abstract (a) Introduction and Objective: Signal transducer and activator of transcription 3 (Stat3) has been implicated in the promotion of migration, invasion and growth of prostate cancer cells. Recently, HDL, which transports the bioactive lipid sphingosine-1-phosphate (S1P), was reported to activate Stat3 in cardiomyocytes and is a known mitogen for several cell types. S1P acts by binding to several G protein-coupled receptors, namely S1P1, S1P2 and S1P3, which are expressed in prostate cancer cell lines. Androgen deprivation therapy in men with prostate cancer leads to a significant increase of HDL-C, but the effect of HDL on prostate cancer is unknown. In this study, we examined the effect of HDL and S1P on Stat3 activation in prostate cancer cells and the involvement of ERK1/2, Akt, and S1P receptors in this process in 3 prostate cancer cell lines (PC-3, LNCaP and DU145). (b) Methods: We used HDL isolated from health volunteer men. Discordial reconstituted(r) HDL containing POPC and apoA-1, (POPC/A-1)rHDL or POPC, S1P and A-1, (POPC/S1P/A-1)rHDL were prepared by the cholate dialysis method. The phosphorylations of Stat3, ERK1/2 and Akt were detected by Western blot analysis. mRNA expressions of PC cells were evaluated by quantitative real-time PCR. Cell viability, migration and invasion were determined by MTS assay, would healing assay and matrigel invasion chamber assay, respectively. (c) Results: HDL increased a dose and a time dependent Ser727 phosphorylation of Stat3, but not Tyr705 in DU145 cells but not in the other two cell lines. S1P and (POPC/S1P/A-1)rHDL also induced the phosphorylation, but not rHDL made without S1P (POPC/A-1). They also induced DU145 cells proliferation, migration, invasion and phosphorylations of ERK1/2 and Akt. PD98059, a MEK inhibitor, and pertussis toxin, a Gi inhibitor, attenuated HDL-, S1P- and (POPC/S1P/A-1)rHDL-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 (POPC/S1P/A-1)rHDL-induced Stat3 phosphorylations and cell migrations. (d) Conclusions: HDL was shown to induce Ser727 phosphorylation of Stat3 via its S1P constituent and involved both S1P2 and S1P3 receptors in DU145 cells. Moreover, ERK1/2 activation is involved in cell activation by HDL. These results suggest that the change in HDL plasma levels by androgen deprivation therapy HDL may alter prostate cancer growth and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5107.