Nicotinamide phosphoribosyltransferase (NAMPT) activity is essential for survival of resting lymphocytes

2013 ◽  
Vol 92 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Maria Pittelli ◽  
Leonardo Cavone ◽  
Andrea Lapucci ◽  
Claudia Oteri ◽  
Roberta Felici ◽  
...  
Keyword(s):  
Nicotinamide Phosphoribosyltransferase ◽  
Resting Lymphocytes

scholarly journals TAMI-08. A TALE OF TWO TELOMERE MAINTENANCE MECHANISMS: TERT EXPRESSION AND THE ALT PATHWAY INDUCE UNIQUE MRS-DETECTABLE METABOLIC REPROGRAMMING IN LOW-GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Pavithra Viswanath ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
Hema Artee Luchman ◽  
Joseph Costello ◽  
...  
Keyword(s):  
Treatment Response ◽  
Metabolic Reprogramming ◽  
Telomere Maintenance ◽  
Imaging Biomarker ◽  
Low Grade ◽  
Tumor Proliferation ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Non Invasive ◽  
Key Enzyme ◽  
Tert Expression

Abstract Telomeres are nucleoprotein structures at chromosomal ends that shorten with cell division and constitute a natural barrier to proliferation. In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism (TMM). Telomerase reverse transcriptase (TERT) expression is the TMM in most tumors, including low-grade oligodendrogliomas (LGOGs). In contrast, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway as their TMM. As molecular hallmarks of tumor proliferation, TMMs are attractive tumor biomarkers and therapeutic targets. Non-invasive imaging of TMM status will, therefore, allow assessment of tumor proliferation and treatment response. However, translational methods of imaging TMM status are lacking. Here, we show that TERT expression and the ALT pathway are associated with unique magnetic resonance spectroscopy (MRS)-detectable metabolic reprogramming in LGOGs and LGAs respectively. In genetically-engineered and patient-derived LGOG models, TERT expression is linked to elevated 1H-MRS-detectable NAD(P)/H, glutathione, aspartate and AXP. In contrast, the ALT pathway in LGAs is associated with higher α-ketoglutarate, glutamate, alanine and AXP. Importantly, elevated flux of hyperpolarized [1-13C]-alanine to pyruvate, which depends on α-ketoglutarate, is a non-invasive in vivo imaging biomarker of the ALT pathway in LGAs while elevated flux of hyperpolarized [1-13C]-alanine to lactate, which depends on NADH, is an imaging biomarker of TERT expression in LGOGs. Mechanistically, the ALT pathway in LGAs is linked to higher glutaminase (GLS), a key enzyme for α-ketoglutarate biosynthesis while TERT expression in LGOGs is associated with elevated nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NADH biosynthesis. Notably, TERT expression and the ALT pathway are linked to MRS-detectable metabolic reprogramming in LGOG and LGA patient biopsies, emphasizing the clinical validity of our observations. Collectively, we have identified unique metabolic signatures of TMM status that integrate critical oncogenic information with noninvasive imaging modalities that can improve diagnosis and treatment response monitoring for LGOG and LGA patients.

Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

2021 ◽  
Author(s):  
Amit Subedi ◽  
Qiang Liu ◽  
Dhanoop M. Ayyathan ◽  
David Sharon ◽  
Severine Cathelin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lipid Homeostasis ◽  
Nicotinamide Phosphoribosyltransferase

DDRE-27. METABOLIC SWITCHING AS A MECHANISM OF DRUG RESISTANCE AGAINST NAMPT INHIBITION IN GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi80-vi80
Author(s):  
Pratibha Sharma ◽  
Vinay Puduvalli
Keyword(s):  
Drug Resistance ◽  
Energy Metabolism ◽  
Cross Reactivity ◽  
Alternative Methods ◽  
Cross Resistance ◽  
Significant Heterogeneity ◽  
Drug Resistant ◽  
High Accumulation ◽  
Metabolic Switch ◽  
Nicotinamide Phosphoribosyltransferase

Abstract BACKGROUND Gliomas exhibit significant heterogeneity in treatment response and characteristically deploy resistance mechanisms that render conventional therapies ineffective. Recently, novel agents have been developed that target regulators of differential energy pathways specifically utilized by gliomas. We previously reported on the targeting of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway and its essential role in glioma cell energy metabolism. Here, we determined the mechanisms by which glioma cells bypass blockade of energy metabolism and develop resistance to NAMPT inhibitors. METHODS Using isogenic parental and drug-resistant patient-derived glioma stem-like cells (GSCs), we examined adaptive changes after NAMPT inhibition in glycolysis, mitochondrial function (oxidative state, basal respiration rate, spare respiratory capacity, maximum respiration capacity and proton leak) and metabolite levels using Agilent Seahorse assay and targeted metabolomics. Cross reactivity across various NAMPT inhibitors was measured using Cell Titer Glo assay. RESULTS GSCs exposed for an extended period to sub-lethal doses of FK866, a potent NAMPT inhibitor, acquired drug resistance to the agent which were also cross-resistant to other NAMPT inhibitors. Drug-resistant GSCs showed a decrease in extracellular acidification rate and oxygen consumption rate compared to isogenic parental lines. Further, metabolomic analysis showed a high accumulation of glutamate, creatine and histidine metabolites in these cells. These results indicate a shift in metabolism of drug-resistant GSCs from carbon metabolism to nitrogen metabolism. CONCLUSIONS GSCs resistant to the NAMPT inhibitor, FK866 showed cross resistance to other NAMPT inhibitors indicating specificity of this effect. The resistance mechanism involves a shift of preferential energy generation from glycolysis to amino acid metabolism which allows the cells to use alternative methods to generate NAD. Additional results from ongoing studies to delineate the mechanisms of metabolic switch in the drug resistance lines will be presented that will help develop strategies to combat resistance to NAMPT inhibitors.

scholarly journals Localization of DNA in the fibrillar components of the nucleolus: a cytochemical and morphometric study.

1993 ◽  
Vol 41 (6) ◽  
pp. 829-836 ◽  
Author(s):  
M Derenzini ◽  
F Farabegoli ◽  
D Trerè
Keyword(s):  
Morphometric Analysis ◽  
Mean Value ◽  
Morphometric Study ◽  
Dense Fibrillar Component ◽  
Thin Sections ◽  
Fibrillar Center ◽  
The Mean ◽  
Fibrillar Component ◽  
Resting Lymphocytes ◽  
The Relationship

We studied the distribution of DNA in human circulating lymphocyte nucleoli using three different cytochemical methods for selective visualization of DNA in thin sections: the Feulgen-like osmium-ammine reaction, the NAMA-Ur procedure, and the osmium-ammine staining in glycine buffer, pH 1.5. All three methods indicated the presence of uniformly distributed, highly decondensed DNA filaments forming a large solitary agglomerate in the central part of the nucleolar area, corresponding to the solitary large fibrillar center (FC) as revealed by uranium and lead staining. We also studied the relationship between DNA agglomerates and nucleolar fibrillar components in resting and phytohemagglutinin (PHA)-stimulated lymphocytes by morphometric analysis of the areas occupied by these structures. In resting lymphocytes the mean area of the DNA agglomerates was 0.479 micron 2 +/- 0.161 SD, whereas that of FCs was 0.380 micron 2 +/- 0.149 SD, with a ratio of 1.26. In PHA-stimulated lymphocytes the mean area of the DNA agglomerates was 0.116 micron 2 +/- 0.056 SD, whereas that of the FCs was 0.075 micron 2 +/- 0.032 SD, with a ratio of 1.55. In PHA-stimulated lymphocytes we also measured the area occupied by the FCs plus the closely associated dense fibrillar component (DFC). The mean value of these two fibrillar components was 0.206 micron 2 +/- 0.081 SD. These data demonstrate that decondensed DNA filaments are uniformly distributed in the FCs and that in transcriptionally active nucleoli they are also present in the proximal portion of the DFC surrounding the FCs.

scholarly journals Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9-R-(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA

1998 ◽  
Vol 42 (3) ◽  
pp. 612-617 ◽  
Author(s):  
Brian L. Robbins ◽  
Ranga V. Srinivas ◽  
Choung Kim ◽  
Norbert Bischofberger ◽  
Arnold Fridland
Keyword(s):  
Human Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Active Metabolite ◽  
Peripheral Blood Lymphocytes ◽  
Activated Lymphocytes ◽  
Blood Lymphocytes ◽  
Virus Activity ◽  
Immunodeficiency Virus ◽  
Resting Lymphocytes ◽  
Pharmacologically Active

ABSTRACT Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

scholarly journals Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma

Oncotarget ◽  
2018 ◽  
Vol 9 (27) ◽  
pp. 18997-19005 ◽  
Author(s):  
Valentina Audrito ◽  
Antonella Managò ◽  
Federica Zamporlini ◽  
Eliana Rulli ◽  
Federica Gaudino ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Nicotinamide Phosphoribosyltransferase

scholarly journals AB1326 Nicotinamide phosphoribosyltransferase may be new factors contributing to osteoarthritis

2018 ◽  
Author(s):  
L. Sivordova ◽  
J. Polyakova ◽  
Y. Akhverdyan ◽  
V. Kravtsov ◽  
N. Fofanova ◽  
...  
Keyword(s):  
Nicotinamide Phosphoribosyltransferase
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