Abstract 3991: Protein phosphatase 2A (PP2A) downregulation is associated with androgen-independent and aggressive phenotypes in prostate cancer

Abstract

Abstract First line of therapy for advanced prostate cancer (PCa) is androgen-deprivation through surgical or chemical castration; however, in majority of cases, tumors relapse in an androgen-independent (AI) form. Once the PCa has recurred in AI form, it progresses to a highly aggressive disease with frequent metastasis and poses an increased risk of morbidity and death. Previously, we demonstrated that PPP2CA, which encodes for alpha-isoform of the protein phosphatase 2A (PP2A) catalytic subunit, is downregulated in prostate cancer. Furthermore, we showed that PP2A activity is inversely associated with AI growth of PCa cells through a novel mechanism, whereby loss of PP2A-mediated checkpoints leads to the activation of Akt and ERK and partially sustains androgen receptor (AR) signaling under steroid-deprived condition. Since AI phenotype of PCa is associated with enhanced metastatic potential, we have investigated, in this study, a role of PPP2CA in the aggressive behavior of the PCa cells. For this, we overexpressed PPP2CA in AI (C4-2 and PC-3) PCa cells, while silenced its expression in AD (LNCaP) PCa cells. We observed that overexpression of PPP2CA in C4-2 and PC-3 cells not only decreased their AI growth and clonogenic ability, but also led to reduced motility and invasion and enhanced cell-cell interaction. Conversely, we observed increased cell motility and invasion and decreased cell-cell interaction upon PPP2CA silencing in LNCaP cells. Immunoblot analyses demonstrated gain of epithelial and loss of mesenchymal markers in PPP2CA-overexpressing PCa cells or vice versa indicating a role of PP2A in opposing epithelial to mesenchymal transition (EMT). Altogether, these studies provide evidence for a functional role of PPP2CA in aggressive behavior of AI PCa cells. 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 3991. doi:1538-7445.AM2012-3991