NAD is an essential coenzyme involved in numerous metabolic pathways and it has been demonstrated that a number of signalling pathways bring about its consumption. Different pathways leading to the formation of NAD are present in cells. Nicotinamide phosphoribosyl transferase (NAMPT), which forms nicotinamide mononucleotide (NMN) from nicotinamide (NM) and PRPP, plays a crucial role in cells to re-use nicotinamide released by NAD-metabolizing enzymes. Moreover, NAMPT has also been described as a cytokine released by immune cells and adipocytes, however the role of NAMPT in the extracellular space is still unclear. The link between NAMPT and cancer is rapidly strengthening. NAMPT has been shown to be involved in angiogenesis and to be up-regulated in a number of solid tumours. Moreover, an important role in tumorigenesis has been postulated for a number of NAD-utilizing enzymes and inhibitors of NAMPT, named FK866 and CHS 828 have entered clinical trails for cancer treatment. In particular, FK866 has entered phase II trial for metastatic melanoma. The aim of our work was to determine the role of NAMPT in melanoma progression and the possibility to use NAMPT inhibitors as anti-cancer agents in melanoma. We investigated the expression of NAMPT in normal nevi, dysplastic nevi and melanoma human samples. Surprisingly, in all melanoma samples and in dysplastic nevi NAMPT is over-expressed, suggesting a possible contribution of this enzyme in melanoma progression. To confirm this data, we investigated the expression of NAMPT in six different melanoma cell lines. All melanoma cells show high levels of NAMPT expression compared to melanocytes. To test if the inhibition of NAMPT was able to decrease melanoma cells viability, we capitalize the action of FK866. However, only one to six melanoma cell line is sensitive to FK866 treatment. To understand why melanoma cells are insensitive to NAMPT inhibition, we investigate MDR expression and the possibility that NAMPT is mutated. Unfortunately, verapamil was not able to increase the sensitivity to FK866 and NAMPT is not mutated in all melanoma cell lines tested, moreover the treatment with FK866 is able to decrease the intracellular NAD level, suggesting that this agent is able to enter cells but not to induce cell death. As NAMPT was described also as a cytokine, we speculate the possibility that melanoma cells are able to release NAMPT in the extracellular space. Indeed, in starvation condition NAMPT is released by melanoma cells in a time-dependent manner. In conclusion, we have demonstrated that NAMPT is over-expressed in human melanoma samples and in melanoma cells, however NAMPT inhibition is not able to affect melanoma cells growth and viability, suggesting that NAMPT up-regulation does not correlate with a pharmacological response. Moreover, NAMPT is released by melanoma cells as a cytokine, we can speculate that NAMPT has a role in the angiogenic process of melanoma progression

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5146. doi:1538-7445.AM2012-5146