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Cytosolic phospholipase A2 increases proliferation, inhibits apoptosis and facilitates angiogenesis in prostate cancer: a potential new therapeutic target
Author(s) -
PATEL M.I.,
KRUEK C.,
YAO M.,
TUCKERMANN R.,
DONG Q.
Publication year - 2006
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2006.06085_19.x
Subject(s) - du145 , lncap , angiogenesis , phospholipase a2 , prostate cancer , apoptosis , cancer research , cell growth , matrigel , cancer cell , biology , chemistry , cancer , medicine , biochemistry , enzyme
The end‐products from the arachadonic acid (AA) pathway have been shown to be tumourigenic in prostate cancer (CaP). Cytosolic phospholipase A2 (cPLA2) is the enzyme that liberates AA from plasma membranes and feeds it to the cycloxygenase and lipoxygenase pathways. In this study we aim to determine the importance of cPLA2 in prostate cancer by examining human prostate cancer specimens and in vitro cell line models. Immunohistochemistry of human prostate specimens revealed that activated cPLA2 levels were significantly higher in prostate cancer compared to benign glands.. Next to determine if inhibition of cPLA2 would lead to decreases in prostate cancer growth, we treated three CaPcell lines (PC3, DU145 and LNCaP) with pyrrolidine 2 (P2), a specific cPLA2 inhibitor and showed it significantly inhibited the growth of all three cell lines at concentrations between 1–10μM by MTS assay. P2 treatment induced a cell cycle block at G0/G1 and a corresponding reduction in BrdU incoprporation by flow cytometry and 3 H‐Thymidine incorporation. In addition cPLA2 knock by siRNA also showed a similar inhibition in proliferation, confirming the importance of cPLA2 in CaP proliferation. P2 also induced apoptosis in CaP cell lines by Caspase 3/7 assay. Treatment of Endothelial cell (HUVECs) cells with P2 had a very significant inhibitory effect on capillary tube formation in matrigel. We conclude that cytosolic phospholipase A2 is overactive in human prostate cancer. It leads to CaP proliferation as well as apoptosis. cPLA2 also is required in endothelial angiogenesis. Inhitibion of cPLA2 by P2 will reduce cancer growth, induce apoptosis and inhibit angiogeneisis in an in vitro model. Together, these findings suggest that cPLA2 could be a potential target in CaP treatment and warrants further validation in animal and human trials.