title: Chemo-sensitizing effects of EP4 receptor-induced inactivation of nuclear factor-κB.
abstract: The EP4 receptor conveys growth-inhibitory effects in mature and immature B cells via NF-κB. Herein, the EP4 receptor was evaluated as a potential therapeutic target for leukemia and lymphoma, whose survival depends on the constitutive activity of NF-κB. Utilizing a pharmacological approach, we proved that the EP4 receptor induces caspase-mediated apoptosis in malignantly transformed B cells, with the most prominent effect being on Burkitt׳s lymphoma cells. Since the increased activation of NF-κB underlies multi-drug resistance phenomena, we modulated this signaling pathway via EP4 receptor triggering. Pge1-OH, a specific EP4 receptor agonist, led to decreased NF-κB activity and a consequent decrease in levels of the antiapoptotic gene Bcl-xL in Ramos cells, resulting in an elevated sensitivity of cells towards bortezomib- and doxorubicin-induced chemotherapeutic effects. Our study identifies the as yet unrecognized potential of EP4 receptor agonists as chemo-sensitizing agents in B-cell lymphoma. The specific downregulation of NF-κB-dependent pathways in B-cell malignancies opens new possibilities for treatment and current therapy optimization using specific EP4 receptor agonists.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Matevž
authors.initials: M
authors.lastname: Prijatelj
authors.affiliation: Institut de Radiobiologie Cellulaire et Moléculaire, Commissariat a l'Energie Atomique (CEA), 18 route du Panorama, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Jozo
authors.initials: J
authors.lastname: Delić
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Markovič
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: irena.mlinaric@ffa.uni-lj.si.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič-Raščan
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051020:bcl-X Protein; D000069286:Bortezomib; D004317:Doxorubicin; D020169:Caspases; D000527:Alprostadil
keywords: Apoptosis; Chemosenzitation; EP(4) receptor; Leukemia; NF-κB