title: Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors.
abstract: OBJECTIVE
  Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth.
  
  
  METHODS
  We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth.
  
  
  RESULTS
  We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition.
  
  
  CONCLUSIONS
  Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer.
authors.affiliation: Authors' Affiliation: Department of Anesthesiology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Claudia C S
authors.initials: CC
authors.lastname: Chini
authors.forename: Anatilde M Gonzalez
authors.initials: AM
authors.lastname: Guerrico
authors.forename: Veronica
authors.initials: V
authors.lastname: Nin
authors.forename: Juliana
authors.initials: J
authors.lastname: Camacho-Pereira
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.forename: Maria Thereza
authors.initials: MT
authors.lastname: Barbosa
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D016207:Cytokines; D008562:Membrane Glycoproteins; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1
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