2026-05-22T11:08:26Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/96132025-05-23T09:55:52Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Mutz, Cornelia N author Schwentner, Raphaela author Aryee, Dave N T author Bouchard, Eric D J author Mejia, Edgard M author Hatch, Grant M author Kauer, Maximilian O author Katschnig, Anna M author Ban, Jozef author Garten, Antje author Alonso, Javier author Banerji, Versha author Kovar, Heinrich author 2017-04-11 Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents with a high metastatic potential. EwS development is driven by a specific chromosomal translocation resulting in the generation of a chimeric EWS-ETS transcription factor, most frequently EWS-FLI1.Nicotinamide adenine dinucleotide (NAD) is a key metabolite of energy metabolism involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability. This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells. Here we report that blocking NAMPT leads to exhaustive NAD depletion in EwS cells, followed by a metabolic collapse and cell death. Using conditional EWS-FLI1 knockdown by doxycycline-inducible shRNA revealed that EWS-FLI1 depletion significantly reduces the sensitivity of EwS cells to NAMPT inhibition. Consistent with this finding, a comparison of 7 EwS cell lines of different genotypes with 5 Non-EwS cell lines and mesenchymal stem cells revealed significantly higher FK866 sensitivity of EWS-ETS positive EwS cells, with IC50 values mostly below 1nM.Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of EwS cells and suggest NAMPT inhibition as a potential new treatment approach for Ewing sarcoma. Oncotarget. 2017 Apr 11;8(15):24679-24693. 10.18632/oncotarget.14976 1949-2553 1949-2553 Oncotarget 28160567 http://hdl.handle.net/20.500.12105/9613 EWS-FLI1 Ewing sarcoma FK866 NAD NAMPT EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells