期刊
ONCOTARGET
卷 8, 期 15, 页码 24679-24693出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14976
关键词
EWS-FLI1; Ewing sarcoma; NAMPT; NAD; FK866
资金
- Austrian Science Fund (FWF) [I1225-B19]
- European Union's FP7 project ASSET [259348]
- Research Manitoba
- CancerCare Manitoba Foundation
- Research Manitoba Graduate Studentship
- Asociacion Pablo Ugarte
- Miguelanez S.A
- ASION-La Hucha de Tomas
- Fundacion La Sonrisa de Alex
- Instituto de Salud Carlos III [PI12/00816]
- Spanish Cancer Network [RTICC RD12/0036/0027]
- Austrian Science Fund (FWF) [I 1225] Funding Source: researchfish
- Austrian Science Fund (FWF) [I1225] Funding Source: Austrian Science Fund (FWF)
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.
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