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Papers In Press, published online ahead of print December 2, 2005
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Institute of Molecular Biology and Genetics, University of Valladolid, Valladolid 47003
Corresponding Author: 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. In order to manipulate the intracellular AA level in U937 phagocytes, we have employed several pharmacological strategies to interfere with the Lands cycle. We have employed 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 have utilized 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.
Revised on December 1, 2005
Accepted on December 2, 2005
Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells
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