Inhibition of calcium-independent phospholipase A2 induces prostate cancer cell cytostasis
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The goal of this work was to identify mechanisms by which inhibition of calcium-independent phospholipase A2 (iPLA2) induces cytostasis in human LNCaP (p53 wild-type and androgen-sensitive) and PC-3 (p53 negative and androgen-insensitive) prostate cancer cells. Both the iPLA2 selective inhibitor bromoenol lactone (BEL) and iPLA2 siRNA induced cytostasis. Cytostasis correlated to a G1/G0 arrest in LNCaP cells and a G2/M arrest in PC-3 cells. In LNCaP cells, G1 arrest was preceded by increases in tumor suppresser protein p53 and p21. In contrast, neither p53 nor p21 was detectable in PC-3 cells, suggesting that BEL activates p21 independently of p53. Further, the iPLA2 selective inhibitor S-BEL had greater affects on cytostasis, phosphorylated (P)-p53 (Ser15), p53 and p21 expression than the iPLA2 inhibitor R-BEL, suggesting that iPLA2 plays more important roles in cytostasis and p53/p21 epxression than iPLA2. BEL decreased cell growth correlated to activation of p38MAPK in both cells. In contrast, BEL only transiently induced ERK in PC-3 cells but not in LNCaP and did not activate JNK in either cell line. Pharmacological inhibition of p38 inhibited BEL-induced increases in P-p53 (Ser15), p53 and p21 as well as G1 arrest in LNCaP cells. BEL treatment also induced reactive species (RS) in PC-3 and LNCaP cells. The antioxidant NAC inhibited BEL-induced RS, p38, p53 and cytostasis in LNCaP cells and attenuated BEL induced RS and cytostasis in PC-3 cells, supporting the hypothesis that RS mediated cytostasis induced by iPLA2 inhibition. Cytostasis induced by iPLA2 inhibition was not reversed by lysophosphatidic acids (LPA) or polyunsaturated fatty acids (PUFA). Thus we tested the hypothesis that iPLA2 inhibition induces cytostasis in prostate cancer cells by altering phospholipid profiles. BEL treatment increased the abundance of unsaturated phosphatidylcholine (PtdCho) and decreased saturated PtdCho without altering phosphatidylserines (PtdSer) or phosphatidylethanolamines (PtdEtn). These results demonstrate that iPLA2 inhibition alters the phospholipid profile of human prostate cancer cells in correlation with induction of cytostasis and identifies the specific phospholipids involved. In conclusion, novel roles of iPLA2 in prostate cancer cell growth and signaling are demonstrated, suggesting that iPLA2 represent a novel therapeutic target for treatment of prostate cancer.