Abstract 3861: Downregulation of protein phosphatase 2A promotes prostate cancer progression and metastasis.
Authors: Bhardwaj Arun , Singh Seema , Srivastava Sanjeev K. , Arora Sumit , Hyde Stephen J. , Honkanen Richard E. , Grizzle William E. , Singh Ajay P. 
Published: August 2014

Clinical progression of prostate cancer (PCa) is characterized by a transition from castration-sensitive (CS) to castration-resistant (CR) phenotype. The resulting CR tumors are highly aggressive and metastatic, and thus pose increased risk of morbidity and death to PCa patients. Therefore, identification of novel gene targets associated with CR growth and metastatic behavior remain a priority area in PCa research. Previously, we identified that PPP2CA, which encodes for the α–isoform of catalytic subunit of PP2A (a serine/threonine phosphatase), is downregulated in CRPCa. In additional findings, we reported that PP2A downregulation sustained the growth of PCa cells under steroid–deprived conditions. In the present study, we examined the role of PP2A in malignant behavior of PCa cells using in vitro and in vivo functional assays. Furthermore, we also delineated the underlying molecular mechanisms. Our data demonstrated that downregulation of PPP2CA (in CS LNCaP cells) promoted, whereas its overexpression (in CR C4-2 and PC3 cells) decreased the migration and invasion of human PCa cells. Similarly, we observed a loss of homotypic interactions in PPP2CA-silenced LNCaP cells, while it increased in PPP2CA-overexpressing C4-2 and PC3 cells. These changes were associated with epithelial to mesenchymal transition (EMT) or vice versa in PPP2CA-silenced or overexpressing PCa cells, respectively. When examined in vivo in an orthotopic mouse model, PPP2CA-overexpressing PC3 cells exhibited dramatic decrease in tumorigenesis due to diminished proliferation and enhanced apoptosis as compared to the control cells. Moreover, significant reduction in metastatic incidence was also observed. Mechanistic studies revealed that PPP2CA downregulation increases nuclear accumulation of β-catenin and NF-κB and subsequent activation of transcriptional activity of the responsive gene promoters. We also observed cooperative involvement of both β-catenin and NF-κB in the PPP2CA downregulation-induced EMT and invasiveness of PCa cells. Lastly, our data demonstrated a role of PP2A/Akt axis in enhanced nuclear accumulation of β-catenin and NF-κB through phosphorylation-induced inactivation of Gsk3-β and IkB-α, respectively. Altogether, our data suggest that loss of PPP2CA is associated with PCa progression and metastasis, and restoration of PP2A activity could serve as an effective preventive and/or therapeutic approach against the advanced disease.

Citation Format: Arun Bhardwaj, Seema Singh, Sanjeev K. Srivastava, Sumit Arora, Stephen J. Hyde, Richard E. Honkanen, William E. Grizzle, Ajay P. Singh. Downregulation of protein phosphatase 2A promotes prostate cancer progression and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2013-3861