Abstract 249: Inhibition of protein phosphatase 2A supports androgen-independent growth of prostate cancer cells

Abstract

Abstract Clinical progression of prostate cancer (PCa) is characterized by a transition from androgen-dependent (AD) to androgen-independent (AI) stage. Once the PCa has recurred in AI form, it progresses to a highly aggressive disease and poses an increased risk of morbidity and death. Therefore, understanding the mechanisms involved in AI progression of PCa is a significant area of research. Earlier, we identified PPP2CA, which encodes for alpha-isoform of the protein phosphatase 2A catalytic subunit (PP2Acα), as one of the downregulated genes in AI PCa cells. PP2A is a ser/thr phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in PCa has not yet been determined. Here, we have investigated the effect of PP2A downregulation on the growth of AD PCa (LNCaP) cells under steroid-deprived condition. Furthermore, we have examined the effect of PP2A inhibition on the signaling pathways and delineated their role in AI growth of LNCaP cells. Our data show that the downregulation of PP2A activity by pharmacological inhibition or siRNA-mediated PPP2CA silencing sustains the growth of AD PCa cells under androgen-deprived condition by relieving the androgen-deprivation-induced cell cycle arrest and preventing apoptosis. Immunoblot analysis revealed enhanced phosphorylation of Akt, ERK, BAD, increased expression of cyclins (cyclin A1 and cyclin D1) and decreased expression of cyclin inhibitor (p27) upon PP2A downregulation. Furthermore, our data show that PP2A inhibition partially maintains AR signaling through its increased expression and ligand-independent phosphorylation, which is also supported by AR transcriptional activity assay and its target gene, KLK3, expression. Pharmacological inhibition of Akt, ERK and AR confirmed a role of these signaling pathways in facilitating the AI growth of LNCaP cells. Altogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 249. doi:10.1158/1538-7445.AM2011-249