Protein Phosphatase 2A Signaling in Human Prostate Cancer

To determine the role of PP2A, a serinethreonine phosphatase, in human prostate cancer PCa progression, we have conducted a series of experiments. Specifically, we have investigated the effect of PP2A activity modulation on androgen-independent AI growth of prostate cancer cells and defined underlying mechanisms. Our data show that the downregulation of PP2A activity by pharmacological inhibition or siRNA-mediated PPP2CA silencing sustains the growth of AD PCa LNCaP 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. These findings are further supported by the effect of ceramide, a potent PP2A activator, on AI PCa C4-2 prostate cancer cells. Ceramide suppresses AI growth of C4-2 cells, which could be rescued by pre-treatment with PP2A inhibitor. Altogether, these initial findings identify a novel PP2A-mediated signaling mechanism that support AI growth of prostate cancer cells.