Abstract 474: The essential role of Giα2 in prostate cancer progression

Abstract

Abstract Basic and clinic research data have suggested that signaling of G-protein-coupled receptors (GPCRs) is amplified in malignant prostate tumors and facilitates the transition of primary cancer cells to the androgen independent stage. Oxytocin (OXT) is a neurohypophyseal peptide hormone that regulates normal prostate functions. However, the information is very limited about the effect of OXT on prostate cancer progression. The effect of OXT is mediated by a GPCR that promiscuously activates multiple G-proteins including Gqα and Giα. Recently, we have shown that OXT receptor (OXTR) is the primary target of OXT in androgen independent prostate cancer cell lines (DU145 and PC3). Moreover, activated OXTR has been shown to promote migration of PC3 cells via a pertussis toxin (PTx) sensitive Gi/o-protein dependent mechanism. In the present study, OXTR was shown to be increased in advanced prostate cancer tissues when compared with normal prostate tissues. Expression of OXTR protein is detected in DU145 and PC3 prostate cancer cell lines but not in the immortalized prostate epithelial cells (RWPE1). OXT treatment (100 nM) inhibited the foskolin (5 µM) induced cAMP accumulation in PC3 cells, as indicated by the cAMP luciferase reporter assay. This data has provided direct evidence that supports the involvement of Giα in the OXTR signaling in PC3 cells. There was no difference in expression of Giα isoforms (Giα1-3) at the mRNA level between normal (PrEC, RWPE1 and RWPE2) and prostate cancer cell lines (LNCaP, DU145, PC3, and PC3M). However, western blot analysis showed that Giα2 is the only Giα family member detectable in PC3 cells. PTx (100 ng/ml) has been shown to abolish the OXT-induced migration of PC3 cells. Overexpression of PTx resistant Giα2, but not wild type Giα2, restored the effect of OXT in PTx pretreated PC3 cells. Accordingly, genetic silencing of Giα2 expression by siRNA eliminated the OXT-induced migration of PC3 cells. Unexpectedly, knock down Giα2 also inhibited the EGF (3 ng/ml) induce migration of PC3 and DU145 cells. In conclusion, Giα2 may play an essential role in prostate cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 474. doi:1538-7445.AM2012-474