Abstract LB-293: High-throughput proteomic analysis identifies protein s as a modulator of high grade and castrate-resistant prostate cancer

Abstract

Abstract High-Throughput Proteomic Analysis Identifies Protein S as a Potential Modulator of Castrate-Resistant Prostate Cancer Punit Saraon, Daniela Cretu, Colm Morrissey, Keith Jarvi, Eleftherios P. Diamandis Androgen-deprivation remains the principal therapy for advanced and metastatic prostate cancers. However, some cancer cells can survive this treatment and transform themselves to a more aggressive androgen-independent prostate cancer (AIPC). An understanding of the molecular alterations that occur during the progression to androgen-independence is an integral step to generate effective targeted therapies. Using Mass Spectrometry, we compared the proteomes of androgen independent cell lines (PC3, DU145, PPC1, LNCaP-SF, 22Rv1) to androgen-dependent (LNCaP, VCaP) and normal prostate epithelial (RWPE) cell lines. We identified more than 100 proteins that were differentially secreted in the androgen independent cell lines, based on spectral counts. Of these, Protein S (PROS1) was elevated in the secretomes of all of the AIPC cell lines, with no detectable secretions in normal and androgen dependent cell lines. Using qPCR, we observed significantly higher tissue expression levels of PROS1 in prostate cancer samples (p<0.05), further indicating its importance in prostate cancer progression. Similarly, immunohistochemistry analysis revealed elevation of PROS1 during high grade prostate cancer (Gleason ≥ 8), and further elevation in castrate-resistant metastatic prostate cancer lesions. We also observed its elevation in high grade prostate cancer seminal plasma samples (P<0.05). To understand the functional role of PROS1 with respect to prostate cancer progression, we generated stable PROS1 knock-downs in DU145 cells, and performed cell migration and viability assays. In-vitro scratch assays measuring cell migration and proliferation revealed that PROS1 enhanced growth of prostate cancer cells, as there was significantly reduced wound closure in shPROS1 DU145 cells compared to scrambled control cells (p<0.05). In addition, cell viability assays showed that shPROS1 cells had reduced survival rates compared to scrambled cells when treated with the chemotherapeutic agents, docetaxel and paclitaxel, indicating its role as a potential anti-apoptotic factor. Taken together, our preliminary results show that PROS1 is elevated during high grade and castrate-resistant prostate cancer, and promotes prostate cancer migration and cell survival. 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 LB-293. doi:1538-7445.AM2012-LB-293