Oncotarget

Research Papers:

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

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 and Heinrich Kovar _

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Oncotarget. 2017; 8:24679-24693. https://doi.org/10.18632/oncotarget.14976

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Abstract

Cornelia N. Mutz1, Raphaela Schwentner1, Dave N.T. Aryee1,5, Eric D.J. Bouchard2, Edgard M. Mejia3, Grant M. Hatch4, Maximilian O. Kauer1, Anna M. Katschnig1, Jozef Ban1, Antje Garten6, Javier Alonso7, Versha Banerji2, Heinrich Kovar1,5

1Children’s Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria

2Department of Biochemistry and Medical Genetics, University of Manitoba, Research Institute in Oncology and Hematology (RIOH), CancerCare Manitoba, Winnipeg, Canada

3Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada

4Department of Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, DREAM Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada

5Department of Pediatrics, Medical University Vienna, Vienna, Austria

6Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

7Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, ISCIII, Ctra, Madrid, Spain

Correspondence to:

Heinrich Kovar, email: [email protected]

Keywords: EWS-FLI1, Ewing sarcoma, NAMPT, NAD, FK866

Received: May 10, 2016     Accepted: January 16, 2017     Published: February 01, 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.


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