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Journal of Lipid Research, Vol. 47, 484-491, March 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells

Rebeca Pérez^*, Xavier Matabosch, Amadeu Llebaria, María A. Balboa^* and Jesús Balsinde^1,*

^* Institute of Molecular Biology and Genetics, Spanish Research Council and University of Valladolid School of Medicine, 47003 Valladolid, Spain
Research Unit on Bioactive Molecules, Institute for Chemical and Environmental Research, Spanish Research Council, 08034 Barcelona, Spain

Published, JLR Papers in Press, December 2, 2005.

¹ To whom correspondence should be addressed. e-mail: jbalsinde{at}ibgm.uva.es

Arachidonic acid (AA) participates in a reacylation/deacylation cycle of membrane phospholipids, the so-called Lands cycle, that serves to keep the concentration of this free fatty acid in cells at a very low level. To manipulate the intracellular AA level in U937 phagocytes, we have used several pharmacological strategies to interfere with the Lands cycle. We used inhibitors of the AA reacylation pathway, namely thimerosal and triacsin C, which block the conversion of AA into arachidonoyl-CoA, and a CoA-independent transacylase inhibitor that blocks the movement of AA within phospholipids. In addition, we used cells overexpressing group VIA phospholipase A₂, an enzyme with key roles in controlling basal fatty acid deacylation reactions in phagocytic cells. All of these different strategies resulted in the expected increase of cellular free AA but also in the induction of cell death by apoptosis. Moreover, when used in combination with any of the aforementioned drugs, AA itself was able to induce apoptosis at doses as low as 10 µM. Blocking cyclooxygenase or lipoxygenases had no effect on the induction of apoptosis by AA. Collectively, these results indicate that free AA levels within the cells may provide an important cellular signal for the onset of apoptosis and that perturbations of the mechanisms controlling AA reacylation, and hence free AA availability, may decisively affect cell survival.

Supplementary key words calcium-independent phospholipase A₂ • deacylation • reacylation • Lands cycle

Abbreviations: AA, arachidonic acid; DAPI, 4',6-diamidino-2-phenylindole; IHP, diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)hepatine phosphonate; iPLA₂-VIA, group VIA calcium-independent phospholipase A₂; lysoPC, lysophosphatidylcholine (1-acyl-2-lyso-sn-glycero-3-phosphocholine); PARP, poly(ADP-ribose) polymerase; PC, choline glycerophospholipid; PLA₂, phospholipase A₂; PS, phosphatidylserine

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