Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma is highly metastatic, and understanding of its molecular mechanism is urgently needed for the development of therapeutic targets and prognostic assessment for metastatic melanoma. SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, belonging to the mammalian sirtuin family. It has been reported that SIRT1 is associated with metastasis in various cancers. However, the molecular mechanism of SIRT1 in melanoma metastasis remains to be clarified. Here we report that SIRT1 induces the epithelial-mesenchymal transition (EMT) by accelerating E-cadherin degradation via autophagy and facilitates melanoma metastasis. Initially, we found that SIRT1 expression was frequently elevated in metastatic melanoma compared with primary melanoma. In addition, SIRT1 induced the EMT and promoted cell migration and invasion by decreasing E-cadherin expression. Further work demonstrated that SIRT1 accelerated the autophagic degradation of E-cadherin through deacetylation of Beclin 1. In addition, inhibition of autophagy recovered E-cadherin expression and suppressed cell migration and invasion by delaying the degradation of E-cadherin in SIRT1-overexpressing cells. Overall, our findings reveal a novel molecular mechanism for SIRT1 in melanoma metastasis, indicating that SIRT1 may serve as a viable therapeutic target for metastatic melanoma.
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PMID:SIRT1 induces epithelial-mesenchymal transition by promoting autophagic degradation of E-cadherin in melanoma cells. 2937 54

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.
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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.
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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.
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PMID:Subcellular Characterization of Nicotinamide Adenine Dinucleotide Biosynthesis in Metastatic Melanoma by Using Organelle-Specific Biosensors. 3145 14