Physiological and pathophysiological roles of NAMPT and NAD metabolism

Garten, Antje; Schuster, Susanne; Penke, Melanie; Gorski, Theresa; Giorgis, Tommaso de; Kieß, Wieland

doi:10.1038/nrendo.2015.117

Cited by 531 publications

(509 citation statements)

References 186 publications

(212 reference statements)

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“…NAMPT is expressed at high levels in several different cancers and, therefore, this enzyme has been considered a potential therapeutic cancer target (5,9,27). Recent studies in glioblastoma have indicated specific genetic subgroups may be exquisitely sensitive to NAMPT inhibition (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3,4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5,6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes.…”

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confidence: 99%

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…For a review of the many apparent functions of human nicotinamide phosphoribosyltransferase, consult the article by Garten and colleagues (269). It is unclear if the many functions may be ascribed simply to variations in the NAD pool.…”

Section: Reactions At the Anomeric Carbon Of Prppmentioning

confidence: 99%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

166

187

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SUMMARY Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.

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“…Recently, several lines of evidence have implicated the critical roles of NAD in a broad range of biological functions. NAD participates in the transduction of numerous important intracellular signalling pathways and controls cell proliferation, death, metabolism, circadian rhythms and ageing (Garten et al, 2015;. The effects of NAD on a group of NAD-dependent proteins, such as the sirtuin family of proteins and PARP1, are the main mechanisms behind NAD's biological functions (Garten et al, 2015;Zhang et al, 2016;Jokinen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

Wei

Kong

Xia

et al. 2017

British J Pharmacology

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Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischaemia; however, a major limitation of tPA is the haemorrhagic transformation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. EXPERIMENTAL APPROACHMiddle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h. When the filament was removed for reperfusion, tPA was infused via the tail vein. A single dose of NMN was injected i.p. (300 mg·kg À1 ). Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins (TJPs) and the activity/expression of MMPs. KEY RESULTSIn the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB.

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Physiological and pathophysiological roles of NAMPT and NAD metabolism

Cited by 531 publications

References 186 publications

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

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Physiological and pathophysiological roles of NAMPT and NAD metabolism

Cited by 531 publications

References 186 publications

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma