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Biochem. J. (2007) 406 (427–436) (Printed in Great Britain)

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Inhibition of calcium-independent phospholipase A₂ suppresses proliferation and tumorigenicity of ovarian carcinoma cells

Yuanda SONG*, Palmer WILKINS*, Wenhui HU†, Karnam S. MURTHY†, Jing CHEN*, Zendra LEE*, Regina OYESANYA*, Jinhua WU*, Suzanne E. BARBOUR* and Xianjun FANG*¹

*Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, U.S.A., and †Department of Physiology, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.

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.

Key words: calcium-independent phospholipase A₂, cell cycle, growth autonomy, lysophosphatidic acid, ovarian cancer cell, tumorigenesis.

Abbreviations used: BEL, bromoenol lactone; EGF, epidermal growth factor; FBS, foetal bovine serum; GFP, green fluorescent protein; HEK-293 cells, human embryonic kidney cells; LPA, lysophosphatidic acid; PLA₂, phospholipase A₂; cPLA₂, cytosolic PLA₂; iPLA₂, calcium-independent PLA₂; shRNA, small-hairpin RNA; siRNA, short interfering RNA.

¹To whom correspondence should be addressed, at Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Box 980614, 1101 East Marshall Street, Richmond, VA 23298, U.S.A. (email xfang@vcu.edu).

Received 15 May 2007; accepted 8 June 2007

Published as BJ Immediate Publication 8 June 2007, doi:10.1042/BJ20070631

© The Authors Journal compilation © 2007 Biochemical Society