Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/9613
EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells
Oncotarget. 2017 Apr 11;8(15):24679-24693.
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.
Acrylamides | Bone Neoplasms | Cell Line, Tumor | Cytokines | Drug Resistance, Neoplasm | Enzyme Inhibitors | HeLa Cells | Humans | NAD | Nicotinamide Phosphoribosyltransferase | Oncogene Proteins, Fusion | Piperidines | Proto-Oncogene Protein c-fli-1 | RNA-Binding Protein EWS | Sarcoma, Ewing
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