pPLAsub2/sub (phospholipase Asub2/sub) enzymes play critical roles in membrane phospholipid homoeostasis and in generation of lysophospholipid growth factors. In the present study, we show that the activity of the cytosolic iPLAsub2/sub (calcium-independent PLAsub2/sub), but not that of the calcium-dependent cPLAsub2/sub (cytosolic PLAsub2/sub), is required for growth-factor-independent, autonomous replication of ovarian carcinoma cells. Blocking iPLAsub2/sub activity with the pharmacological inhibitor BEL (bromoenol lactone) induces cell cycle arrest in S- and Gsub2/sub/M-phases independently of the status of the p53 tumour suppressor. Inhibition of iPLAsub2/sub activity also leads to modest increases in apoptosis of ovarian cancer cells. The S- and Gsub2/sub/M-phase accumulation is accompanied by increased levels of the cell cycle regulators cyclins B and E. Interestingly, the S-phase arrest is released by supplementing the growth factors LPA (lysophosphatidic acid) or EGF (epidermal growth factor). However, inhibition of iPLAsub2/sub activity with BEL remains effective in repressing growth-factor- or serum-stimulated proliferation of ovarian cancer cells through Gsub2/sub/M-phase arrest. Down-regulation of iPLAsub2/subβ expression with lentivirus-mediated RNA interference inhibited cell proliferation in culture and tumorigenicity of ovarian cancer cell lines in nude mice. These results indicate an essential role for iPLAsub2/sub in cell cycle progression and tumorigenesis of ovarian carcinoma cells./p
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