Abstract 3315: RON-mediated hijacking of AR signaling in androgen-independent prostate cancer

Abstract

Abstract Despite significant progress in developing effective strategies for management of localized prostate cancer, the 5-year survival for metastatic castrate-resistant disease is less than 30%. Previous studies from our own and other laboratories showed the anti-tumorigenic potential of 2-Methoxyestradiol (2-ME2) in various tumor models. Although variety of mechanisms including anti-angiogenic, pro-apoptotic, cell cycle deregulation has been reported to contribute to 2-ME2-mediated biological effects, the precise mechanism is unclear. To explore the role of 2-ME2, we carried out gene expression array analysis and discovered Recepteur d’Origine Nantais (RON) as one of the most significantly down regulated gene in response to 2-ME2 treatment. Subsequently, RON was found to be significantly upregulated in advanced-stage PCA cell lines, which do not express androgen receptor (AR); and high-grade human prostate tumors. Stable silencing of RON in androgen independent, PTEN-/- PC3 cells showed noticeable changes in cell morphology, actin filament organization, as well as markers of epithelial-to-mesenchymal transition (EMT). In PTEN wild type DU145 cells, RON knockdown caused an increase in AR expression and promoter activity but decreased the transcriptional activation and expression of AR target genes such as PSA. In contrast, RON overexpression in androgen-responsive LNCAP cells leads to a suppression of the transcriptional activation of both AR and its downstream targets, including PSA. Furthermore, we found that RON silencing decreases expression and promoter activity of the anti-apoptotic protein FLICE-like inhibitory protein (FLIP) that is accompanied by the induction of apoptosis. In addition, intervention with 2-ME2 reduced tumor growth that is accompanied with decreased RON expression in the prostate in transgenic adenocarcinoma of mouse prostate (TRAMP) model. These observations implicate RON as a hijacker of AR signaling that contributes in part to PCA growth. Therefore, restoration of native AR signaling via RON targeting could possibly be exploited in combination with antiandrogenic therapy to prevent recurrence of castrate-resistant prostate cancer. Supported by CA135451 (APK). Citation Format: Izhar Singh Batth, Peng Meng, Roble Bedolla, Robert E. Reddick, Addanki Pratap Kumar. RON-mediated hijacking of AR signaling in androgen-independent prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3315. doi:10.1158/1538-7445.AM2014-3315