Effects of 2-deoxyglucose and dehydroepiandrosterone on intracellular NAD+ level, SIRT1 activity and replicative lifespan of human Hs68 cells

Yang, Nae-Cherng; Song, Tuzz-Ying; Chen, Mei-Yau; Hu, Miao‐Lin

doi:10.1007/s10522-011-9342-7

Cited by 25 publications

(21 citation statements)

References 37 publications

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“…To investigate how severe energy depletion affects Sirt1 activity, we replaced glucose (25 mM) with 2-DG (25 mM) rather than adding 2-DG to the glucose-containing media44. Two hours later, we visualized deacetylation of three Sirt1 substrates, p53 (K382) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

et al. 2017

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Sirt1 is an NAD+-dependent protein deacetylase that regulates many physiological functions, including stress resistance, adipogenesis, cell senescence and energy production. Sirt1 can be activated by energy deprivation, but the mechanism is poorly understood. Here, we report that Sirt1 is negatively regulated by ATP, which binds to the C-terminal domain (CTD) of Sirt1. ATP suppresses Sirt1 activity by impairing the CTD's ability to bind to the deacetylase domain as well as its ability to function as the substrate recruitment site. ATP, but not NAD+, causes a conformational shift to a less compact structure. Mutations that prevent ATP binding increase Sirt1's ability to promote stress resistance and inhibit adipogenesis under high-ATP conditions. Interestingly, the CTD can be attached to other proteins, thereby converting them into energy-regulated proteins. These discoveries provide insight into how extreme energy deprivation can impact Sirt1 activity and underscore the complex nature of Sirt1 structure and regulation.

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Section: Resultsmentioning

confidence: 99%

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

et al. 2017

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“…The inhibition of ER stress induction by 2‐DG at 10 μM concentration may be partially due to the increased SIRT‐1 expression [Ghemrawi et al, ]. A study by Yang et al [] has revealed SIRT‐1 to be a redox sensor, dependent on the metabolic status of the cell. They have reported that, in fibroblasts, 2‐DG causes activation of SIRT‐1 in a NAD + dependent manner, mimicking a calorie restriction effect.…”

Section: Discussionmentioning

confidence: 99%

2-Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT-1 Dependent Mechanism

et al. 2016

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Reprogramming of energy metabolism particularly switching over of cells to aerobic glycolysis leading to accumulation of lactate is a hallmark of cancer. Lactate can induce angiogenesis, an important process underlying tumor growth and metastasis. VEGF is one of the most important cytokines which regulate this process and the present study was designed to examine if blocking glycolytic pathway in tumor cells can affect its angiogenic potency with respect to VEGF. For this, the expression and biological activity of VEGF synthesized and secreted by tumor derived cell lines in the presence or absence of 2-deoxy glucose (2-DG), an inhibitor of glycolysis was determined. The results suggested that inhibition of glycolysis using sub-lethal doses of 2-DG down-regulated the expression of VEGF and also significantly reduced its biological activity. Further mechanistic studies revealed that the down regulation of VEGF gene expression by 2-DG was due to an increase in SIRT-1 activity and the reduced biological activity was found to be due to an increase in the PAR modification of VEGF. Activity of SIRT-1 and PAR modification of VEGF in turn, was found to be correlated to the cellular NAD levels. The results presented here therefore suggest that treatment of cancer cells with 2-DG can significantly reduce its overall angiogenic potency through transcriptional and post-translational mechanisms. J. Cell. Biochem. 118: 252-262, 2017. © 2016 Wiley Periodicals, Inc.

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“…It has been hypothesized that CR, by increasing the levels of intracellular NAD, could stimulate SIRTUIN activity, and then extend the lifespan of organisms, (Lin et al, 2000; Longo et al, 2015; Lu and Lin, 2010). Recently, it was reported that a CR mimetic, 2-deoxyglucose (2-DG), can extend the replicative lifespan of Hs68 cells by increasing intracellular NAD and SIRT1 activity (Yang et al, 2011). However, several other mechanisms, independent of SIRTUINS, have also been implicated in the biological effects of CR, including inhibition of the IGF-1 pathway and modulation of the AMPK-mTOR pathway (Longo et al, 2015).…”

Section: Interventions To Prevent Age-related Nad Declinementioning

confidence: 99%

NAD and the aging process: Role in life, death and everything in between

Chini

Tarragó

Chini

2017

Molecular and Cellular Endocrinology

168

188

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Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD). From the simplest organism, such as bacteria, to the most complex multicellular organisms, NAD is a key cellular component. NAD is extremely abundant in most living cells and has traditionally been described to be a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD has also been shown to play a key role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin. Thus, NAD is a molecule that provides an important link between signaling and metabolism, and serves as a key molecule in cellular metabolic sensoring pathways. Importantly, it has now been clearly demonstrated that cellular NAD levels decline during chronological aging. This decline appears to play a crucial role in the development of metabolic dysfunction and age-related diseases. In this review we will discuss the molecular mechanisms responsible for the decrease in NAD levels during aging. Since other reviews on this subject have been recently published, we will concentrate on presenting a critical appraisal of the current status of the literature and will highlight some controversial topics in the field. In particular, we will discuss the potential role of the NADase CD38 as a driver of age-related NAD decline.

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Effects of 2-deoxyglucose and dehydroepiandrosterone on intracellular NAD+ level, SIRT1 activity and replicative lifespan of human Hs68 cells

Cited by 25 publications

References 37 publications

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

2-Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT-1 Dependent Mechanism

NAD and the aging process: Role in life, death and everything in between

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