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A Nampt inhibitor FK866 mimics vitamin B3 deficiency by causing senescence of human fibroblastic Hs68 cells via attenuation of NAD(+)-SIRT1 signaling.
- Source :
-
Biogerontology [Biogerontology] 2015 Dec; Vol. 16 (6), pp. 789-800. Date of Electronic Publication: 2015 Sep 02. - Publication Year :
- 2015
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Abstract
- Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.
- Subjects :
- AMP-Activated Protein Kinases metabolism
Cell Line
Cell Proliferation drug effects
Cellular Senescence physiology
Enzyme Inhibitors pharmacology
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts metabolism
Glutathione metabolism
Humans
NAD pharmacology
NADP metabolism
Niacin pharmacology
Niacinamide pharmacology
Signal Transduction drug effects
TOR Serine-Threonine Kinases metabolism
Tumor Suppressor Protein p53 metabolism
Acrylamides pharmacology
Cellular Senescence drug effects
Cytokines antagonists & inhibitors
NAD metabolism
Niacinamide deficiency
Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
Piperidines pharmacology
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-6768
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biogerontology
- Publication Type :
- Academic Journal
- Accession number :
- 26330291
- Full Text :
- https://doi.org/10.1007/s10522-015-9605-9