EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells.
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.
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.
Cornelia N
CN
Mutz
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.
Raphaela
R
Schwentner
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University Vienna, Vienna, Austria.
Dave N T
DNT
Aryee
Department of Biochemistry and Medical Genetics, University of Manitoba, Research Institute in Oncology and Hematology (RIOH), CancerCare Manitoba, Winnipeg, Canada.
Eric D J
EDJ
Bouchard
Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Edgard M
EM
Mejia
Department 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.
Grant M
GM
Hatch
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.
Maximilian O
MO
Kauer
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.
Anna M
AM
Katschnig
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.
Jozef
J
Ban
Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Antje
A
Garten
Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, ISCIII, Ctra, Madrid, Spain.
Javier
J
Alonso
Department of Biochemistry and Medical Genetics, University of Manitoba, Research Institute in Oncology and Hematology (RIOH), CancerCare Manitoba, Winnipeg, Canada.
Versha
V
Banerji
Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University Vienna, Vienna, Austria.
Heinrich
H
Kovar
D000178:Acrylamides / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
D000178:Acrylamides; D016207:Cytokines; C106031:EWS-FLI fusion protein; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
EWS-FLI1; Ewing sarcoma; FK866; NAD; NAMPT