TY - JOUR T1 - Inhibition of Ca<sup>2+</sup>-Independent Phospholipase A<sub>2</sub> Decreases Prostate Cancer Cell Growth by p53-Dependent and Independent Mechanisms JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 59 LP - 68 DO - 10.1124/jpet.108.138958 VL - 326 IS - 1 AU - Bin Sun AU - Xiaoling Zhang AU - Sonia Talathi AU - Brian S. Cummings Y1 - 2008/07/01 UR - http://jpet.aspetjournals.org/content/326/1/59.abstract N2 - The mechanisms by which Ca2+-independent phospholipase A2 (iPLA2) mediates cell growth in p53-positive LNCaP and p53-negative PC-3 prostate cancer cell lines were studied. Exposure of cells to the iPLA2 selective inhibitor bromoenol lactone (BEL; 0–20 μM) induced concentration- and time-dependent decreases in cell growth based on 3-(4, dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide staining and cell number. Decreased cell growth was not caused by cell death as BEL exposure did not alter nuclear morphology or increase annexin V (apoptotic cell marker) or propidium iodide (necrotic cell marker) staining after 48 h. Decreased growth correlated to a G1/G0 arrest in LNCaP cells and aG2/M arrest in PC-3 cells. In LNCaP cells, G1 arrest was preceded by time- (0–48 h) and concentration-dependent (0–10 μM) increases in the expression of the tumor suppresser protein p53 and the cyclin-dependent kinase inhibitor p21. Increases in p53 expression preceded increases in p21 expression by 8 h. In LNCaP cells, BEL treatment decreased the expression of the p53 antagonist Mdm2, while increasing Akt phosphorylation. BEL treatment also increased Akt phosphorylation in PC-3 cells, but Mdm2 was not detected. The ability of BEL to increase Akt phosphorylation was inhibited by the phosphoinositide 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]. BEL treatment also decreased agonist-induced activation of the epidermal growth factor receptor. These data suggest that inhibition of iPLA2 decreases prostate cancer cell growth by p53-dependent and independent mechanisms. Furthermore, alterations in Mdm2 and epidermal growth factor receptor activation following BEL exposure suggest novel roles for iPLA2 in prostate cancer cell signaling. The American Society for Pharmacology and Experimental Therapeutics ER -