The NAD metabolome — a key determinant of cancer cell biology

Chiarugi, Alberto; Dölle, Christian; Felici, Roberta; Ziegler, Mathias

doi:10.1038/nrc3340

Cited by 485 publications

(493 citation statements)

References 129 publications

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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%

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.

100

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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%

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.

100

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“…However, excessive glycolysis seemed to perturb NAD þ metabolism, which is an essential cofactor for DNA repair enzymes such as the Sirtuin and PARP family members. 46 Therefore, excessive glycolysis may contribute to genomic instability in cancer cells and maintenance of glycolysis in an optimal range could be important for DNA repair capacity.…”

Section: Discussionmentioning

confidence: 99%

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Chen

Wang²,

Bai

et al. 2014

Cell Death Differ

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Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy. A cell's metabolism is optimized for its function and adapts to environmental changes; therefore, it is pivotal to differentiation, proliferation, survival and death. In the presence of ample oxygen, cancer cells prefer glycolysis over mitochondrial respiration for energy supply, which is known as the Warburg effect or aerobic glycolysis.1,2 Although aerobic glycolysis was originally thought to complement impaired mitochondrial respiration, recent investigations suggest that it is a driving force in cancer cell transformation and proliferation. 3,4 In coordination with the tricarboxylic acid cycle and mitochondrial respiration, cancer cells increase glycolysis to support their rapid proliferation. This 'metabolic transformation' in cancer cells not only meets their energy requirements but also provides the building blocks for synthesis of biomass and for maintenance of redox homeostasis. 5,6 Thus, the metabolic transformation is believed to offer cancer cells a selective growth advantage compared with their normal counterparts and to contribute to drug resistance. Many oncogenes such as c-Myc and Akt, and tumor suppressors such as p53 are involved in the regulation of glycolysis and mitochondrial metabolism, serving as evidence of the necessity for metabolic adaptation in cancer cells. 7,8 However, how metabolic transformation is precisely regulated needs further elucidation.Receptor-interacting protein 1 (RIP1) is a serine/threonine kinase with functions in cell proliferation, survival and death.9-11 The role of RIP1 in cell survival is achieved mainly through its function as an adaptor in signal pathways, such as NF-kB and PI3K/Akt, that suppress apoptosis. The kinase activity of RIP1 is involved in programmed necrosis or necroptosis.12 Although RIP1 can translocate to the mitochondria in certain circumstances and can modulate ADP/ ATP exchange and the production of mitochondrial reactive oxygen species (ROS), [13][14][15][16] whether RIP1 regulates cell energy homeostasis is unknown.In an attempt to investigate the role of RIP1 in cell proliferation, we uncovered a function for this protein in...

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“…[3][4][5][6] Nicotinamide adenine dinucleotide (NAD), as well as its precursors, derivatives, and metabolic enzymes, has recently drawn much attention as regards a variety of biological functions including transcriptional regulation, DNA repair, cell cycle progression, metabolism, lifespan, and cell death. 7 Typically, (i) sirtuin 1 (SIRT1) is an NAD-dependent protein deacetylase; (ii) poly(ADP-ribose) polymerase-1 (PARP1) as a sensor of DNA damage catalyzes the transfer of ADPribose units from NAD to target proteins; (iii) nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for NAD biosynthesis, which together comprise a system of regulatory networks, termed the 'NAD World', that maintains the balance of cellular metabolism and has essential roles in tumor development and therapy.…”

Section: Xiu-xia Wang and Da LImentioning

confidence: 99%

Linking BRCA1 to NAD World

Wang¹,

2015

Cell Cycle

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The NAD metabolome — a key determinant of cancer cell biology

Cited by 485 publications

References 129 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

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Linking BRCA1 to NAD World

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The NAD metabolome — a key determinant of cancer cell biology

Cited by 485 publications

References 129 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

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Linking BRCA1 to NAD World

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Product

Resources

About

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