Inhibition of calcium-independent phospholipase A2 suppresses proliferation and tumorigenicity of ovarian carcinoma cells.
PLA2 (phospholipase A2) 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 iPLA2 (calcium-independent PLA2), but not that of the calcium-dependent cPLA2 (cytosolic PLA2), is required for growth-factor-independent, autonomous replication of ovarian carcinoma cells. Blocking iPLA2 activity with the pharmacological inhibitor BEL (bromoenol lactone) induces cell cycle arrest in S- and G2/M-phases independently of the status of the p53 tumour suppressor. Inhibition of iPLA2 activity also leads to modest increases in apoptosis of ovarian cancer cells. The S- and G2/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 iPLA2 activity with BEL remains effective in repressing growth-factor- or serum-stimulated proliferation of ovarian cancer cells through G2/M-phase arrest. Down-regulation of iPLA2b 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 iPLA2 in cell cycle progression and tumorigenesis of ovarian carcinoma cells.
Song
Yuanda
Y
Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
Wilkins
Palmer
P
Hu
Wenhui
W
Murthy
Karnam S
KS
Chen
Jing
J
Lee
Zendra
Z
Oyesanya
Regina
R
Wu
Jinhua
J
Barbour
Suzanne E
SE
Fang
Xianjun
X
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D016213:Cyclins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D054522:Group VI Phospholipases A2; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D016213:Cyclins; D008246:Lysophospholipids; D009281:Naphthalenes; D011753:Pyrones; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D054467:Phospholipases A2; C516476:Pla2g6 protein, mouse; C032881:lysophosphatidic acid; D002118:Calcium