Award Number : W 81 XWH - 09 - 1 - 0137 TITLE : Protein Phosphatase 2 A Signaling in Human Prostate Cancer

Earlier we identified PPP2CA, which encodes for the a-isoform of protein phosphatase 2A (PP2A) catalytic subunit, as one of the downregulated genes in androgen-independent prostate cancer. PP2A is a serine/threonine phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in prostate canc•er has not yet been determined. Here, we have investigated the effect of PP2A activity modulation on the androgen-independent growth of prostate cancer cells. Our data show that the PPP2CA expression and PP2A activity is downregulated in androgenindependent (C4-2) prostate cancer cells as compared with androgen-dependent (LNCaP) cells. Downregulation of PP2A activi ty by pharmacologic inhibition or short interfering RNA-mediated PPP2CA silencing sustains the growth of LNCaP cells under an androgen-deprived condition by relieving the androgen deprivation-induced cell-cycle arrest and preventing apoptosis. lmmunoblot analyses reveal enhanced phosphory'lation of Akt, extracellular signal-regulated kinase (ERK), BAD, increased expression of cyclins (A 1/D 1 ), and decreased expression of cycli n inhibitor (p27) on PP2A downregulation. Furthermore, our dat.a show that androgen receptor (AR) signaling is partially maintained in PP2A-inhibi ted cells through inc reased AR expression and ligand-independent phosphorylation. Pharmacologic inhibition of Akt, ERK, and AR suggest a role of these signaling pathways in facilitating the androgen-independent growth of LNCaP cells. These observations are supported by the effect of ce ramide, a PP2A ac tivator, on androgen-independent C4-2 ce lls. Ceramide inhibited the growth of C4-2 cells on androgen deprivation, an effect that could be abrogated by PP2A downregulation. A ltogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer. PMID: 21393425 [PubMedindexed for MEDLINE) PMCID: PMC3669395 Free PMC Article Images from this publication. See all images (61 Free text Publication TYpes, MeSH Terms, Substances, Grant Support · ·.: · ~J.: 1 ~ ··r ::.:::::.:" I illll -.::;.:" I IY> ~ ~ ~-: , ·o~ ---, "'<\,#'