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Query: UMLS:C0278883 (
metastatic melanoma
)
6,224
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Metastatic melanoma
carrying BRAF mutations represent a still unmet medical need as success of BRAF inhibitors is limited by development of resistance.
Nicotinamide phosphoribosyltransferase
(
NAMPT
) is a key enzyme in NAD biosynthesis. An extracellular form (eNAMPT) possesses cytokine-like functions and is up-regulated in inflammatory disorders, including cancer. Here we show that eNAMPT is actively released in culture supernatants of melanoma cell lines. Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Plasma from mice xenografted with BiR cell lines contain higher eNAMPT levels compared to tumor-free animals. Consistently, eNAMPT levels are elevated in 113 patients with BRAF-mutated
metastatic melanoma
compared to 50 with localized disease or to 38 healthy donors, showing a direct correlation with markers of tumor burden, such as LDH, or aggressive disease (such as PD-L1). eNAMPT concentrations decrease in response to therapy with BRAF/MEK inhibitors, but increase again at progression, as inferred from the serial analysis of 50 patients. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival. Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with
metastatic melanoma
carrying BRAF mutations.
...
PMID:Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma. 2972 Nov 78
Cancer cells rewire their metabolism to support proliferation, growth and survival. In
metastatic melanoma
the BRAF oncogenic pathway is a master regulator of this process, highlighting the importance of metabolic reprogramming in the pathogenesis of this tumor and offering potential therapeutic approaches. Metabolic adaptation of melanoma cells generally requires increased amounts of NAD
+
, an essential redox cofactor in cellular metabolism and a signaling molecule.
Nicotinamide phosphoribosyltransferase
(
NAMPT
) is the most important NAD
+
biosynthetic enzyme in mammalian cells and a direct target of the BRAF oncogenic signaling pathway. These findings suggest that
NAMPT
is an attractive new therapeutic target, particularly in combination strategies with BRAF or MEK inhibitors. Here we review current knowledge on how oncogenic signaling reprograms metabolism in BRAF-mutated melanoma, and discuss how
NAMPT
/NAD
+
axis contributes to these processes. Lastly, we present evidence supporting a role of
NAMPT
as a novel therapeutic target in
metastatic melanoma
.
...
PMID:Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT). 3105 16
Aim:
Nicotinamide adenine dinucleotide (NAD
+
) plays central roles in a wide array of normal and pathological conditions. Inhibition of NAD
+
biosynthesis can be exploited therapeutically in cancer, including melanoma. To obtain quantitation of NAD
+
levels in live cells and to address the issue of the compartmentalization of NAD
+
biosynthesis, we exploited a recently described genetically encoded NAD
+
biosensor (LigA-circularly permutated Venus), which was targeted to the cytosol, mitochondria, and nuclei of
BRAF-V600E
A375 melanoma cells, a model of
metastatic melanoma
(MM).
Results:
FK866, a specific inhibitor of
nicotinamide phosphoribosyltransferase
(
NAMPT
), the main NAD
+
-producing enzyme in MM cells, was used to monitor NAD
+
depletion kinetics at the subcellular level in biosensor-transduced A375 cells. In addition, we treated FK866-blocked A375 cells with NAD
+
precursors, including nicotinamide, nicotinic acid, nicotinamide riboside, and quinolinic acid, highlighting an organelle-specific capacity of each substrate to rescue from
NAMPT
block. Expression of NAD
+
biosynthetic enzymes was then biochemically studied in isolated organelles, revealing the presence of
NAMPT
in all three cellular compartments, whereas nicotinate phosphoribosyltransferase was predominantly cytosolic and mitochondrial, and nicotinamide riboside kinase mitochondrial and nuclear. In keeping with biosensor data, quinolinate phosphoribosyltransferase was expressed at extremely low levels.
Innovation and Conclusions:
Throughout this work, we validated the use of genetically encoded NAD
+
biosensors to characterize subcellular distribution of NAD
+
production routes in MM. The chance of real-time monitoring of NAD
+
fluctuations after chemical perturbations, together with a deeper comprehension of the cofactor biosynthesis compartmentalization, strengthens the foundation for a targeted strategy of NAD
+
pool manipulation in cancer and metabolic diseases.
...
PMID:Subcellular Characterization of Nicotinamide Adenine Dinucleotide Biosynthesis in Metastatic Melanoma by Using Organelle-Specific Biosensors. 3145 14
