TY - JOUR A1 - Wobst, Ivonne A1 - Ebert, Lisa A1 - Birod, Kerstin A1 - Wegner, Marthe-Susanna A1 - Hoffmann, Marika A1 - Thomas, Dominique Jeanette A1 - Angioni, Carlo Federico A1 - Parnham, Michael J. A1 - Steinhilber, Dieter A1 - Tegeder, Irmgard A1 - Geisslinger, Gerd A1 - Grösch, Sabine T1 - R-Flurbiprofen traps prostaglandins within cells by inhibition of multidrug resistance-associated protein-4 T2 - International journal of molecular sciences N2 - R-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 cPLA2α 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. KW - flurbiprofen KW - MRP4 KW - cPLA2 KW - PGE2 Y1 - 2017 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44127 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-441278 SN - 1422-0067 SN - 1661-6596 N1 - © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). VL - 18 IS - Art. 68 SP - 1 EP - 16 PB - Molecular Diversity Preservation International CY - Basel ER -