Oncol Rep. 2017 Sep;38(3):1767-1773. doi: 10.3892/or.2017.5793. Epub 2017 Jul 6.

Inhibition of NAMPT decreases cell growth and enhances susceptibility to oxidative stress.

Xu R1, Yuan Z2, Yang L3, Li L1, Li D1, Lv C4.

Author information

1School of Nursing, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.2Library, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.3Cancer Research Institute, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.4Department of Respiratory Medicine, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.

Abstract

Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10 nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells. Quantitative proteomics revealed that 325 proteins were downregulated in the FK866-treated cells, and were involved in diverse cellular processes including nucleobase-containing compound metabolic process, protein metabolic process, antioxidant and DNA repair processes. Downregulation of 4 selected proteins was confirmed by western blotting and quantitative PCR. Downregulation of antioxidant proteins GRX1 and catalase, and DNA-repair proteins PCNA and PARP1 contributed to the enhanced susceptibility of FK866-treated cells to oxidative stress. FK866 treatment also caused mitochondrial dysfunction through downregulation of mitochondrial ribosomal proteins. Taken together, these results demonstrate that FK866 treatment efficiently decreases the cellular NAD level and induces autonomous changes in proteostasis, leading to cell growth inhibition and increased susceptibility to oxidative stress.

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