Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer

Cancer Lett. 2016 Aug 28;379(1):1-11. doi: 10.1016/j.canlet.2016.05.024. Epub 2016 May 24.

Abstract

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment.

Keywords: Aerobic glycolysis; NAD; Nampt; Pancreatic cancer; miR-206.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Acrylamides / pharmacology*
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Binding Sites
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / antagonists & inhibitors*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gemcitabine
  • Glycolysis / drug effects
  • Humans
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • NAD / metabolism*
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Piperidines / pharmacology*
  • RNA Interference
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 3' Untranslated Regions
  • Acrylamides
  • Antimetabolites, Antineoplastic
  • Cytokines
  • Enzyme Inhibitors
  • MIRN206 microRNA, human
  • MicroRNAs
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • NAD
  • Deoxycytidine
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • Gemcitabine