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EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells.
- Source :
-
Oncotarget [Oncotarget] 2017 Apr 11; Vol. 8 (15), pp. 24679-24693. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Bone Neoplasms drug therapy
Bone Neoplasms enzymology
Bone Neoplasms metabolism
Cell Line, Tumor
Cytokines metabolism
Drug Resistance, Neoplasm
HeLa Cells
Humans
NAD metabolism
Nicotinamide Phosphoribosyltransferase metabolism
Sarcoma, Ewing drug therapy
Sarcoma, Ewing enzymology
Sarcoma, Ewing metabolism
Sarcoma, Ewing pathology
Acrylamides pharmacology
Cytokines antagonists & inhibitors
Enzyme Inhibitors pharmacology
Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
Oncogene Proteins, Fusion metabolism
Piperidines pharmacology
Proto-Oncogene Protein c-fli-1 metabolism
RNA-Binding Protein EWS metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28160567
- Full Text :
- https://doi.org/10.18632/oncotarget.14976