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Docosahexaenoic Acid Induces Increases in [Ca²⁺]_i via Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase C and - via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells

Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 4183–Lipides & Signalisation Cellulaire, Faculty of Life Sciences, University of Burgundy, Dijon, France (V.A., A.H., A.P., N.A.K.); and Institut National de la Santé etdela Recherche Médicale U866, Ecole Pratique des Hautes Etudes, University of Burgundy, Dijon, France (R.F., C.R., A.B.)

We investigated, in monocytic leukemia U937 cells, the effects of docosahexaenoic acid (DHA; 22:6 n-3) on calcium signaling and determined the implication of phospholipase C (PLC) and protein kinase C (PKC) in this pathway. DHA induced dose-dependent increases in [Ca²⁺]_i, which were contributed by intracellular pool, via the production of inositol-1,4,5-triphosphate (IP₃) and store-operated Ca²⁺ (SOC) influx, via opening of Ca²⁺ release-activated Ca²⁺ (CRAC) channels. Chemical inhibition of PLC, PKC, and PKC, but not of PKC I/II, PKC, or PKCI, significantly diminished DHA-induced increases in [Ca²⁺]_i. In vitro PKC assays revealed that DHA induced a 2-fold increase in PKC and - activities, which were temporally correlated with the DHA-induced increases in [Ca²⁺]_i. In cell-free assays, DHA, but not other structural analogs of fatty acids, activated these PKC isoforms. Competition experiments revealed that DHA-induced activation of both the PKCs was dose-dependently inhibited by phosphatidylserine (PS). Furthermore, DHA induced apoptosis via reactive oxygen species (ROS) production, followed by caspase-3 activation. Chemical inhibition of PKC/ and of SOC/CRAC channels significantly attenuated both DHA-stimulated ROS production and caspase-3 activity. Our study suggests that DHA-induced activation of PLC/IP₃ pathway and activation of PKC/, via its action on PS binding site, may be involved in apoptosis in U937 cells.

Address correspondence to: N. A. Khan, Directeur, UPRES EA4183 Lipids and Signalisation Cellulaire, Université de Bourgogne, Faculté des Sciences de la Vie, 6 Bd Gabriel, 21000 Dijon, France. E-mail: naim.khan{at}u-bourgogne.fr