The mechanisms by which Ca(2+)-independent phospholipase A(2) (iPLA(2)) mediates 
cell growth in p53-positive LNCaP and p53-negative PC-3 prostate cancer cell 
lines were studied. Exposure of cells to the iPLA(2) selective inhibitor 
bromoenol lactone (BEL; 0-20 microM) 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 G(1)/G(0) arrest in LNCaP cells and aG(2)/M arrest in PC-3 cells. In LNCaP 
cells, G(1) arrest was preceded by time- (0-48 h) and concentration-dependent 
(0-10 microM) increases in the expression of the tumor suppressor 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 iPLA(2) 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 iPLA(2) in prostate cancer cell signaling.