Fiche publication
Date publication
décembre 2007
Journal
Molecular pharmacology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BETTAIEB Ali
,
Dr REBE Cédric
,
Pr KAHN Naim
,
Dr HICHAMI Aziz
,
Dr AIRES Virginie
Tous les auteurs :
Aires V, Hichami A, Filomenko R, Plé A, Rébé C, Bettaieb A, Khan NA
Lien Pubmed
Résumé
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, PKCgamma, and PKCdelta, but not of PKCbeta I/II, PKCalpha, or PKCbetaI, significantly diminished DHA-induced increases in [Ca2+]i. In vitro PKC assays revealed that DHA induced a approximately 2-fold increase in PKCgamma and -delta 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 PKCgamma/delta 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 PKCgamma/delta, via its action on PS binding site, may be involved in apoptosis in U937 cells.
Mots clés
Apoptosis, drug effects, Binding Sites, drug effects, Calcium Signaling, drug effects, Docosahexaenoic Acids, metabolism, Enzyme Activation, drug effects, Humans, Inositol 1,4,5-Trisphosphate, biosynthesis, Intracellular Fluid, metabolism, Phosphatidylserines, chemistry, Protein Kinase C, chemistry, Protein Kinase C-delta, chemistry, U937 Cells
Référence
Mol. Pharmacol.. 2007 Dec;72(6):1545-56