Journal
BIOCHEMICAL JOURNAL
Volume 406, Issue -, Pages 427-436Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20070631
Keywords
calcium-independent phospholipase A(2); cell cycle; growth autonomy; lysophosphatidic acid; ovarian cancer cell; tumorigenesis
Categories
Funding
- NCI NIH HHS [CA102196, P30 CA16059, P30 CA016059, R01 CA102196] Funding Source: Medline
- NINDS NIH HHS [F31 NS051090] Funding Source: Medline
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PLA(2) (phospholipase A(2)) 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 iPLA(2) (calcium-independent PLA(2)), but not that of the calcium-dependent cPLA(2) (cytosolic PLA(2)), is required for growth-factor-independent, autonomous replication of ovarian carcinoma cells. Blocking iPLA(2) activity with the pharmacological inhibitor BEL (bromoenol lactone) induces cell cycle arrest in S- and G(2)/M-phases independently of the status of the p53 tumour suppressor. Inhibition of iPLA(2) activity also leads to modest increases in apoptosis of ovarian cancer cells. The S- and G(2)/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 iPLA(2) activity with BEL remains effective in repressing growth-factor- or serum-stimulated proliferation of ovarian cancer cells through G(2)/M-phase arrest. Down-regulation of iPLA(2)beta 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 iPLA(2) in cell cycle progression and tumorigenesis of ovarian carcinoma cells.
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