Inhibition of Ca2+-independent phospholipase A2 decreases prostate cancer cell growth by p53-dependent and independent mechanisms.
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.
Sun
Bin
B
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
Zhang
Xiaoling
X
Talathi
Sonia
S
Cummings
Brian S
BS
D002118:Calcium / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D064801:Phospholipase A2 Inhibitors; D011753:Pyrones; D016159:Tumor Suppressor Protein p53; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D054467:Phospholipases A2; D002118:Calcium