Wobst, I.I.WobstEbert, L.L.EbertBirod, K.K.BirodWegner, M.-S.M.-S.WegnerHoffmann, M.M.HoffmannThomas, D.D.ThomasAngioni, C.C.AngioniParnham, M.J.M.J.ParnhamSteinhilber, D.D.SteinhilberTegeder, I.I.TegederGeisslinger, G.G.GeisslingerGrösch, S.S.Grösch2022-03-052022-03-052017https://publica.fraunhofer.de/handle/publica/24727910.3390/ijms18010068R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2a to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance-associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.en547journal article