EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells

نویسندگان

  • Cornelia N. Mutz
  • Raphaela Schwentner
  • Dave N.T. Aryee
  • Eric D.J. Bouchard
  • Edgard M. Mejia
  • Grant M. Hatch
  • Maximilian O. Kauer
  • Anna M. Katschnig
  • Jozef Ban
  • Antje Garten
  • Javier Alonso
  • Versha Banerji
  • Heinrich Kovar
چکیده

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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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017