Abstract
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
Highlights
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life
Cellular NAD levels decline with age, whereas supplementation with NAD precursors exert a protective role to slow down aging and prevent metabolic and neurodegenerative disease
NAD is largely consumed via nonredox NAD-dependent enzymes such as poly(ADP-ribose) polymerases (PARPs), ADPribose transferases, NADase, and sirtuins, which use NAD and generate nicotinamide, whereas nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme to convert nicotinamide back to NAD
Summary
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion This significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). NAD is a substrate of PARP for ADP-ribosylation of nuclear proteins in cellular stress responses [21, 22] that regulate cell proliferation, death, differentiation, and senescence All these findings suggest that NAD is essential for cellular metabolism, mitochondrial function, stress response, From the ‡MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China; §Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; ¶Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, 100043, China. A recent study found that CD38 increases with age and dictates age-dependent NAD decline [36]
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