Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.
Cancer Lett
; 379(1): 1-11, 2016 08 28.
Article
in En
| MEDLINE
| ID: mdl-27233476
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Piperidines
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Acrylamides
/
Cytokines
/
Drug Resistance, Neoplasm
/
Carcinoma, Pancreatic Ductal
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Deoxycytidine
/
Enzyme Inhibitors
/
Nicotinamide Phosphoribosyltransferase
/
NAD
Type of study:
Prognostic_studies
Language:
En
Journal:
Cancer Lett
Year:
2016
Type:
Article
Affiliation country:
United States