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CELLULAR AND MOLECULAR

Inhibition of Ca²⁺-Independent Phospholipase A₂ Decreases Prostate Cancer Cell Growth by p53-Dependent and Independent Mechanisms

Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia

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.