|Year : 2018 | Volume
| Issue : 4 | Page : 109-116
Nicotinamide phosphoribosyltransferase: Biology, role in cancer, and novel drug target
Antonio Lucena-Cacace1, Amancio Carnero2
1 Instituto De Biomedicina De Sevilla (IBIS) (HUVR, CSIC, Universidad De Sevilla), Sevilla, Spain; Ciber De Cáncer; Department Cell Growth and Differentiation, Center For iPS Cell Research and Application (CIRA) Kyoto University, Kyoto, Japan
2 Instituto De Biomedicina De Sevilla (IBIS) (HUVR, CSIC, Universidad De Sevilla), Sevilla, Spain; Ciber De Cáncer, Center For iPS Cell Research and Application (CIRA) Kyoto University, Kyoto, Japan
|Date of Submission||08-Jun-2018|
|Date of Acceptance||16-Aug-2018|
|Date of Web Publication||31-Aug-2018|
Dr. Amancio Carnero
Instituto De Biomedicina De Sevilla/HUVR/CSIC, Hospital Universitario Virgen Del Rocio, Avda. Manuel Siurot S/n, 41013, Sevilla, Spain
Source of Support: None, Conflict of Interest: None
The nicotinamide adenine dinucleotide (NAD+) pool is an important electron exchanger in tumor biology. The salvage pathway plays an important role in the regulation of the levels of cellular NAD+ biosynthesis and the nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of this pathway. Thus, NAMPT plays a key role in the levels of the NAD+ pool. NAMPT levels in several types of cancer, both solid and hematological cancers, are found to be high compared to the normal tissue. In these tumors, NAMPT overexpression induces an increase in tumorigenic properties. Increased transcription levels of NAMPT result in an increased rate of growth, resistance to cell death, and epidermal-to-mesenchymal transition imparting cancer stem cell-like properties in tumorigenic cells. Main stemness signaling pathways such as Notch, Hippo, Sonic, and Wnt are associated with increased NAMPT transcription levels. NAMPT-induced oncogenic phenotype is also associated with worse prognosis and resistance to therapy in human tumors. Therefore, NAMPT could be an interesting enzyme to consider as probable therapeutic target.
Keywords: Cancer stem cells, nicotinamide adenine dinucleotide, nicotinamide phosphoribosyltransferase, salvage pathway, therapy resistance
|How to cite this article:|
Lucena-Cacace A, Carnero A. Nicotinamide phosphoribosyltransferase: Biology, role in cancer, and novel drug target. Cancer Transl Med 2018;4:109-16
|How to cite this URL:|
Lucena-Cacace A, Carnero A. Nicotinamide phosphoribosyltransferase: Biology, role in cancer, and novel drug target. Cancer Transl Med [serial online] 2018 [cited 2019 Jun 27];4:109-16. Available from: http://www.cancertm.com/text.asp?2018/4/4/109/240293
| Introduction|| |
Cell respiration and most of cellular signaling process rely on oxidation-reduction reactions. These reactions often rely on the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH and the oxidation of NADH to NAD+. Imbalance in the oxidation-reduction reactions are directly linked to several diseases including cancer, therefore, maintaining the balance of these reactions is critical.,,
The process of pathogenesis or tumor initiation that results in cancer is a multiphasic process. This process comprises the acquisition of certain characteristics that include independence to growth signals, insensitivity to cellular antiproliferative signals, resistance to apoptosis, unlimited replicative potential, increased vascularization, increased invasiveness into adjacent tissues, immune system evasion, and deregulation of tumor metabolism. All these tumor characteristics, in common, depend on the recycling of NAD+ as the primary electron exchanger in the reduction-oxidation reaction.
NAD+ is a water-soluble coenzyme that plays a key role in reduction-oxidation reactions during cellular metabolism., It is, in fact, a universal electron transporter yielding ATP-derived energy in catabolic process and thus, maintaining cellular homeostasis.
NAD+ is reduced to NADH in a reversible reaction when embracing a hydride ion (H-, constituted by one proton and two electrons) from an oxidizable substrate [Figure 1]. When NADH releases its electrons, the NAD+ form is recovered in order to behave as an enzymatic cofactor setting an electron donor-acceptor loop., In this way, the free energy produced by the oxidation of the substrates is conserved. Both NAD+ and its near-analog nicotinamide adenine dinucleotide phosphate (NADP+) are composed of two nucleotides attached through their phosphate groups through a phosphoanhydride bond [Figure 1].
NAD+ has a preferential role in catabolic reactions such as oxidation reactions such as combustion of pyruvate, fatty acids, and α-ketoacids.
The process where NAD+ is used is often spatially separated by cell organelles. While those already aforementioned take place in the mitochondrial matrix, those ones involving reductive biosynthesis, including fatty acids, synthesis take place in the cytosol. Such spatial and functional specialization allows the cells to have two independent electron carriers' pools involving different functions. More than 200 cellular enzymes using NAD+ or NADP+ have been described as acceptors of hydride ions from some reduced substrate to catalyze their reactions. That is why NAD+, its metabolism and recycling, play a fundamental role in the maintenance of cellular homeostasis.,,,,
| Nicotinamide Adenine Dinucleotide Metabolism|| |
Four major molecules are used as substrates for the synthesis of NAD+. These molecules are dietary tryptophan (L-Trp), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR).
|Figure 1: Nicotinamide adenine dinucleotide oxidative state. nicotinamide adenine dinucleotide is transformed into NADH by accepting a proton and two electrons. Alternatively, NADH can be transformed into a phosphorylated analog (NADPH) by the addition of an extraphosphate group|
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These four large molecules are involved in the synthesis of NAD+ through two major pathways: de novo pathway and salvage Pathway. Some metabolic intermediates such as nicotinamide mononucleotide (NMN) might also stimulate the direct synthesis of NAD+ [Figure 2].,
De novo synthesis of NAD+ takes place intracellularly in an eight-step reaction.,,,, This pathway takes the L-Trp acquired through daily diet as a conversion molecule when obtaining NAD+. Tryptophan-derived quinolinic acid is produced and used by quinolinate phosphoribosyltransferase (NAPT) to form NA mononucleotide (NAMN). NAMN is converted to NA adenine mononucleotide (NAAD) in an NMN adenylyltransferase (NMNAT)-mediated reaction with ATP consumption. There are three isoforms of NMNAT (NMNAT 1-3) in different tissue and cellular locations depending on the metabolic requirements. NMNAT-1 is a ubiquitously expressed nuclear protein. NMNAT-2 is normally present in the Golgi apparatus and the cytosol.,,,, NMNAT-3 may be present in both the cytosol and mitochondrial compartments. The efficiency of obtaining NAD+ by dietary tryptophan is very low compared to that obtained by the salvage pathway.
This NAD+ synthesis pathway is also known as the Preiss–Handler pathway. In this pathway, the NAD+ is generated from niacin (Vitamin B3) in a three-step reaction. NAM can also be a precursor of NAD+ through its conversion to NMN by the limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). NMN acts as an intermediate by catalyzing the reversible addition of a ribose group from 5-phosphoribosyl-D-ribosyl-1-pyrophosphate to NAM. In the mitochondrial respiratory chain, NADH acts as the main donor of electrons, which ends up in the generation of ATP by oxidative phosphorylation.,,
The liver is the major organ involving NAD+ metabolic activity as it expresses all enzymes needed for either metabolism or recycling. Hepatic cells can actually convert all its precursors: NA, NAM, and their ribosides as well as L-Trp. For that, NAMPT and NAPRT mRNA levels are particularly high in liver, making this organ one of the major NAD+ recycling and synthesis engine cores in humans.,
All tissues have the potential to at least convert NAM and NR into NAD+. That is why the NAMPT enzyme and at least two NMNAT isoforms are ubiquitously expressed in all cells and tissues, while NMNAT2 is brain specific. Other NMNAT isoforms are expressed in a greater proportion in the pancreas, thyroid gland, and lymphocytes. In mammalian cells, the metabolism of NAD+ is compartmentalized. The formation of NAD+ from NMN takes place in the nucleus and in the mitochondria,, [Figure 3]. These two organelles are particularly important as the most important NAD+-dependent intracellular signaling pathways occur in them.
The most important cytosolic NAD+ precursor for mitochondrial synthesis is NMN. Therefore, NAD+-dependent cellular processes are intimately linked to the most important molecular events that could lead to cancer: genomic alterations, metabolic imbalances, and changes in the transcription patterns of candidate oncogenes or tumor suppressors.
NAMPT is the limiting enzyme of the NAD+ salvage pathway, the major NAD+ source in living cells, being the major contributor to NAD+ maintenance, recycling, and homeostasis.
NAMPT is a highly conserved protein among mammals. It was cloned and isolated for the first time in the organism Haemophilus ducreyi and it has been extensively studied. It was originally characterized as the human homologous protein pre-B cell colony-enhancer factor (PBEF). In its role as PBEF, it acts as a cytokine, which stimulates early B-cell formation in a synergistic effect with interleukin 7 (IL-7) and stem cell factor., Namptflox/flox-Cre mice displayed a dramatic decrease in thymic cell numbers, FACS analysis of the spleen and lymph node suspensions revealed a near complete loss of peripheral T- and B-cells in mice, confirming the role of NAMPT in B-cell formation.
The gene encoding NAMPT is found on human chromosome 7, specifically at the 7q22.3 locus. The size of the gene within the DNA is 3.7 kilobases (kb) and contains 11 exons and 10 introns that encode a coding DNA of 2.357 kb [Figure 4]. The protein has a weight of 52 kilodaltons (kDa) and contains 491 amino acids (aa). The protein lacks a cellular export signal and also contains 6 cysteine residues, so it has been suggested as a structure similar to zinc finger.
In silico, up to 13 messengers of different NAMPT RNAs (mRNA) are predicted by alternative splicing mechanisms, of which only four have been found at the biological level. Of the four, only the first messenger, translating into the 491 amino acid proteins, is able to make the conversion to its enzymatic product NMN.
NAMPT is expressed in all tissues, with higher levels in bone marrow, liver, and muscle fiber cells, where the energy intake is greater.
PBEF or Visfatin, known as extracellular NAMPT (e NAMPT, as opposed to intracellular NAMPT,i NAMPT), is an adipocytokine that is expressed in visceral fat tissue and its circulating levels correlate with obesity. The extracellular role of NAMPT is unknown and could have a function of activation or silence signaling pathways within the cell other than those related to its enzymatic function.
As a limiting enzyme of the pathway which plays a key role in the maintenance of intracellular NAD+, NAMPT could be an oncogene contributing to the onset, progression, and relapse of Cancer.
| Nicotinamide Phosphoribosyltransferase in Cancer|| |
In solid tumors, NAMPT is overexpressed. These included colorectal, ovarian, breast, gastric, prostate, well-differentiated thyroid cancer, melanoma, glioma, and endometrial carcinoma. Clinically, higher NAMPT expression is associated with worse prognosis correlating with metastases and dedifferentiation in melanoma.,
|Figure 2: Nicotinamide adenine dinucleotide metabolism. Four major synthesis precursors (n, dark blue) are divided between two major pathways. Left half – De novo synthesis pathway. Right half – Salvage pathway|
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|Figure 3: Scheme of cellular pathways using nicotinamide adenine dinucleotide. (a) Main pathways using nicotinamide adenine dinucleotide. (b) Major nicotinamide adenine dinucleotide-mediated deacetylases controlling HIF-1 stabilization and oxidative stress responses|
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|Figure 4: Location and structure of the nicotinamide phosphoribosyltransferase gene. Schematic figure of the long arm of human chromosome 7. DNA gene region including introns and exons is shown|
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High levels of NAMPT have been found in hematological malignancies such as diffuse large B-cell lymphoma, Hodgkin's lymphoma, follicular B-cell lymphoma, and peripheral T-cell lymphoma. In these tumors, it does associate to a more aggressive malignant lymphoma phenotype.
Other enzymes of the salvage pathway have been suggested to be potential therapeutic targets in cancer. Mitochondrial NMNAT3 knockdown had minimal effect over mitochondrial NAD+ levels.,, On the other hand, NMNAT2 cytosolic inhibition decreased mitochondrial NAD+ levels, suggesting that NAD+ in the mitochondrial is partially supported by NAD+ intake from the cytosol. Subsequent studies found that NAMPT inhibition has no effect on mitochondrial NAD+ pool levels, discarding the previous theory and highlighting the role of NAMPT as the main potential target in cancer. NAMPT inhibition seems to be particularly effective on cells harboring naturally high glycolysis.
Upregulation of NAMPT expression in many human cancers highlights its potent role as an oncogene favoring tumor progression. Functional studies reveal that NAMPT contributes to tumor progression favoring tumorigenicity and enriching the CIC phenotype in glioblastoma and colorectal cancer cell lines. For this reason, a considerable load of research is being conducted exploring drug design targeting NAMPT, setting the basis for new generation inhibitors. A recent study published by our laboratory early this year suggests that NAMPT could contribute to colon cancer progression through SIRT1 and PARP1. Sirtuins and PARP proteins are NAD+-dependent, thus NAMPT expression plays a key role modulating their function in colon cancer. Its mechanisms facilitating tumor progression are poorly defined but embrace more mechanisms than SIRT1. In leukemia cells, NAMPT inhibitors show dual inhibition of MTOR/4EBP1 signaling, EIF4E, and EIF2A, which seems to be driven by AMPK activation. Reactive oxygen species (ROS) are known to play a role in DNA damage and cancer. Tumor cells use NADPH as a reducing equivalent to create cytoprotective systems against ROS. As a general mechanism in cancer cells, NAMPT increases NAD+ pool, which is changed to NADPH through the pentose phosphate pathway through NADP+. In prostate cancer, NAMPT inhibits H2O2-induced cell death through the Sirt1-FoxO3a. The NADPH increase enables ROS reduction through glucose deprivation. PARP proteins, as ADP-ribosyltransferases, govern early DNA damage responses, facilitating DNA repair. These proteins have been classically associated to tumor progression in a context-dependent manner. NAMPT expression seems to depend on Sirtuins and PARP proteins to contribute to its tumoral phenotype. Therefore, NAD+ modulation through NAMPT is emerging as a valuable tool to regulate Sirtuin and PARP1 function in cancer.,,
Functional studies using specific shRNAs against NAMPT proved to reduce tumorigenicity and attenuate cancer stem cell-like (CSC-like) phenotype. In the same way than glioma tumors, NAMPT defines a gene profile involving effectors for stemness and EMT maintenance. Most gastric cancer cell lines displaying a high expression profile of EMT markers are extremely vulnerable to inhibition of NAMPT, in particular on NAPRT deficiency context. Although the mechanisms defining the role of NAMPT enhancing the EMT phenotype remain unclear, it is possible that these markers are highly sustained energetically by NAD+ pool. Along with SIRT1 and PARP1 as mediators, NAMPT expression defines a new profile comprising YAP1, MYC, DVL2, MMP7, CSNK2A1, and ADAM17 as end-points of CSC pathway activation.
Data mining and NGS analyses reveal a strong correlation between PARP and SIRT proteins with NAMPT expression related to the augmentation of tumorigenic properties. The aforementioned profile enables response to treatment and accurately stratifies prognosis. This profile seems to be independent of the levels of intracellular NAD+, opposing to previous studies on the field. NAMPT inhibitor FK866 offers a better response when strengthened with sirtinol or olaparib (SIRT1 and PARP1 inhibitors, respectively) in combination therapies. In vitro, tumorspheres with high levels of NAMPT have shown critical sensitivity to NAMPT inhibitors, indicating that NAMPT inhibition may be a suitable therapy for colorectal cancer too. This benefit may come from attenuation of cancer progression, decrease in CICs subset, and alleviation of relapse incidence. Attenuation of these features also sensitizes to antineoplastic therapies.
NAMPT seems to be a suitable therapeutic target, especially on those patients who express the genetic profile driven by its expression. Therefore, NAMPT expression potentially predicts good responders to its inhibitors, with a particular effect on advanced colon cancer with increased CICs subset. However, we will still have to deal with toxicity issues, since other inhibitors have proven to be highly toxic in human trials.
Nicotinamide phosphoribosyltransferase-based drug development
Further, NAMPT level has been associated with increased chemoresistance to certain therapeutic agents such as doxorubicin, paclitaxel, etoposide, fluorouracil, and phenylethyl isothiocyanate., Many studies have shown that NAD+ depletion by NAMPT inhibition causes cell death through apoptosis. Many proapoptotic proteins were found activated when NAMPT was inhibited in leukemias, multiple myeloma, breast cancer, and lymphoma cells. It has been found that NAMPT inhibition-mediated apoptosis requires functional apoptotic machinery because blocking apoptosis with several factors such as L-type calcium channels with verapamil or nimodipine, caspase 3 with Z-Asp-Glu-Val-Asp-fluoromethylketone, caspase 9 with Z-Leu-Glu-His-Asp-fluoromethylketone, or the mitochondrial permeability transition with bongkrekic acid blocks the effect of NAMPT inhibition-mediated apoptosis.,,
NAMPT is also an immune suppressive microenvironment promoter. NAMPT increases expression of IL-10 immunosuppressive cytokines. In addition, it does enhance expression of tumor-promoting cytokines such as IL-6 and IL-8. NAMPT inhibitors were proved to have positive therapeutic response on synergy with other drugs targeting suppression promoting enzymes. APO866, a NAMPT inhibitor, synergizes with L-1MT, and IDO inhibitor, where the later demonstrably enhance immune response over tumor cells and reduce tumor volume in mice. According to this data, testing immunomodulators or immune checkpoint inhibitors in patients with high NAPMT levels in tumors might be a plausible strategy in combination to suboptimal doses of NAMPT inhibitors.
Three NAMPT inhibitors (APO866/FK866, GMX1778, and GMX1777) entered clinical trials and completed phase I, however, further evaluation was discontinued primarily due to dose-limiting toxicities (ClinicalTrials.govidentifiers: NCT00457574, NCT00724841, NCT00432107, NCT00435084, NCT00431912).
Homozygous NAMPT knockout proved to be lethal within 10 days in adult mice. Eight enzymes in tricarboxylic acid accompanied by 25 % body weight loss indicate that mice lethality is caused by exhaustion of body fats driven by short supply of ATP. These results point out that NAMPT is, indeed, an essential gene for life. ATP shortage impaired intestinal structure and villous atrophy. This fact could partially explain why NAMPT inhibitors were discontinued by side effects including severe gastrointestinal symptoms.
Altogether, these data indicate that alternative administration routes or dosage modulation may ultimately minimize unwanted side effects, achieving better therapeutic efficacy.
| Conclusions|| |
NAMPT is a highly conserved protein across mammalian species and lower organisms with a key role in metabolism. It has been described that NAMPT is overexpressed in many types of tumor. It has been proven that NAMPT expression triggers a potent pleiotropic effect, with high impact on tumor progression, relapse, and exerting influence over EMT processes and maintaining signaling pathways controlling CIC-like features.
Meta-analysis of the overall survival of patients related to NAMPT expression reveals that NAMPT may ultimately be a suitable prognosis biomarker in a broader spectrum of cancer types, including sarcomas, lymphomas, and myeloma [Figure 5].
It will be crucial to understanding the underlying biology of NAMPT, generating new generation of inhibitors reducing its associated toxicity, and targeting the fine balance between tissue homeostasis and cancer driven by NAD+ levels.
Financial support and sponsorship
AC lab was supported by grants from the Spanish Ministry of Economy and Competitivity, Plan Estatal de I+D+I 2013-2016, ISCIII (Fis: PI15/00045) and CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2014). Especial thanks to the AECC Foundation for supporting this work.
|Figure 5: Overall survival for nicotinamide phosphoribosyl transferase expression. (a) GSE3141 for lung tumors. (b) GSE63157 for Ewing Sarcoma. (c) GSE93291 for mantle cell lymphoma. (d) TCGA for pancreatic adenocarcinoma. (e) GSE2658 for myeloma tumors. (f) GSE45547 for neuroblastoma tumors|
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]