Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells.
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 A(2), 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 muM. 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.
Pérez
Rebeca
R
Institute of Molecular Biology and Genetics, Spanish Research Council and University of Valladolid School of Medicine, 47003 Valladolid, Spain.
Matabosch
Xavier
X
Llebaria
Amadeu
A
Balboa
María A
MA
Balsinde
Jesús
J
D000214:Acyl Coenzyme A / Q000378:metabolism; D000215:Acylation; D000217:Acyltransferases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004951:Esterification / Q000187:drug effects; D054522:Group VI Phospholipases A2; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D020298:U937 Cells / Q000378:metabolism*
D000214:Acyl Coenzyme A; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010743:Phospholipids; C026563:arachidonyl-coenzyme A; D016718:Arachidonic Acid; D000217:Acyltransferases; C039766:arachidonyl transacylase; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human