CD73 Protein as a Source of Extracellular Precursors for Sustained NAD+ Biosynthesis in FK866-treated Tumor Cells

Grozio, Alessia; Sociali, Giovanna; Sturla, Laura; Caffa, Irene; Soncini, Debora; Salis, Annalisa; Raffaelli, Nadia; Flora, Antonio De; Nencioni, Alessio; Bruzzone, Santina

doi:10.1074/jbc.m113.470435

Cited by 135 publications

(137 citation statements)

References 57 publications

(61 reference statements)

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“…Evidence of extracellular conversion of NAD and NMN to NR by the ectocellular enzymes CD38 and CD73 also exists ( Figure 2). [16][17][18] By analysing tissue sources of 719 cDNA clones, NAMPT was found to be expressed in nearly all organs, tissues and cells examined. 1,19 This ubiquitous expression of NAMPT suggests pleiotropic functions of the protein in human physiology.…”

Section: Physiological Role Of Namptmentioning

confidence: 99%

“…[173][174][175][176][177][178][179][180] One possible explanation could be that CD38 or CD73 reverse cell death induced by NAMPT inhibition through the supply of ectocellular NAD precursors. 18 However, combining FK866 or other NAMPT inhibitors with antineoplastic agents, chemotherapy or radiotherapy might enhance their therapeutic efficacy. 181 Conclusion Levels of NAD are decreased in various metabolic disorders and during ageing.…”

Section: Nampt In Cancermentioning

confidence: 99%

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Physiological and pathophysiological roles of NAMPT and NAD metabolism

et al. 2015

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Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.

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Section: Physiological Role Of Namptmentioning

confidence: 99%

Section: Nampt In Cancermentioning

confidence: 99%

Physiological and pathophysiological roles of NAMPT and NAD metabolism

et al. 2015

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“…NR can also be generated via the enzyme CD73 (cluster of differentiation 73), an ecto-5'-nucleotidase. The CD73 catalytic site faces the outside of the cell and mediates the synthesis of NR from NAD and NMN, contributing to the availability of NR for intracellular synthesis of NAD (Figure 3) (Grozio et al, 2013). …”

Section: Nad Metabolismmentioning

confidence: 99%

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

Chini

Tarragó

Chini

2017

Molecular and Cellular Endocrinology

158

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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“…Localization of ecto-Ca-ATPase and 5′-ectonucleotidase activities was shown in caveolae of smooth muscle cells of the guinea-pig vas deferens and their role in neurotransmission has been suggested (Kittel & Bacsy, 1994). Interestingly, it has recently been proposed that human CD73 (which carries out 5′-nucleotidase activity) is capable of processing NAD + and its metabolite NMN (Garavaglia et al, 2012; Grozio et al, 2013), suggesting novel pathways in NAD + metabolism. The possible role of these enzymatic pathways in metabolism of neurally released NAD + has not been determined.…”

Section: Termination Of Neurotransmitter Actionmentioning

confidence: 99%

The purinergic neurotransmitter revisited: A single substance or multiple players?

Mutafova‐Yambolieva

Durnin

2014

Pharmacology & Therapeutics

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The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout.

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CD73 Protein as a Source of Extracellular Precursors for Sustained NAD+ Biosynthesis in FK866-treated Tumor Cells

Abstract: Background: NAMPT inhibitors showed antitumor activity in preclinical cancer models, but no tumor remission occurred in clinical studies. Results: Cells treated with a NAMPT inhibitor are rescued by low NAD

Cited by 135 publications

References 57 publications

Physiological and pathophysiological roles of NAMPT and NAD metabolism

Physiological and pathophysiological roles of NAMPT and NAD metabolism

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

The purinergic neurotransmitter revisited: A single substance or multiple players?

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