Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide–consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry–based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer) and HCT-116 (colorectal cancer) cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA), and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC)-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.
Highlights
As a continuation to a previous study on the pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) describing the metabolic basis of NAMPT inhibition [1], we report here the results of a global metabolomics analysis that revealed the metabolic alterations of NAMPT inhibition in human cancer cells
We have shown that NAMPT inhibition leads to numerous metabolic perturbations in cancer cells and demonstrated resourcefulness of global metabolomics as a useful data extraction protocol for studying cellular metabolism
The profound effects of NAMPT inhibition on cancer cell metabolism could serve as a basis for further understanding of the physiological role of NAMPT in cancer cell metabolism
Summary
As a continuation to a previous study on the pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) describing the metabolic basis of NAMPT inhibition [1], we report here the results of a global metabolomics analysis that revealed the metabolic alterations of NAMPT inhibition in human cancer cells. Recent studies have demonstrated that NAMPT-mediated NAD biosynthesis in cancer cells plays a crucial role in several physiological processes, including metabolism, energy generation, survival, apoptosis, DNA repair, and inflammation [2, 12,13,14]. It has been adequately reported that NAD turnover in cancer or proliferating cells is significantly increased over healthy or non-proliferating cells [1, 7]. These observations on the possible involvement of NAMPT in disease have been supported by various approaches in cancer cells studies [10,11,12,13,14]. NAMPT exemplifies a promising therapeutic target for the development of potential novel cancer drugs
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