Review
The role of nitric oxide in melanoma

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Abstract

Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself.

Section snippets

Mechanisms of nitric oxide production in melanoma

Nitric oxide (NO) is a free radical inorganic signaling molecule that is generated via multiple mechanisms (Fig. 1). One of these mechanisms catalyzed by nitric oxide synthase (NOS) is the oxidation reaction of L-arginine and oxygen with a NADPH co-substrate to produce L-citrulline and NO [1]. There are 3 isotypes of NOS in humans: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2) and endothelial NOS (eNOS or NOS3). iNOS is transcriptionally induced by immunologic stimuli produced by

Conclusion

Although NO is primarily understood to be a gaseous signaling molecule, the evidence illustrates that NO has a multifaceted role in the development of melanoma. NO mediates effects through the melanoma cell itself, immune cell subsets (e.g. MDSC, DC, cytotoxic T cells, tumor associated macrophages), and the tumor microenvironment (e.g. vasculature, lymphatics). A dichotomy in this paper has been established in that NO can have both tumor promoting and inhibitory effects. Many of these effects

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Acknowledgements

J. Markowitz receives support from the Donald A Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center and is also an Assistant Professor in the USF Morsani College of Medicine Department of Oncologic Sciences. The research was supported in part by the National Cancer Institute, part of the National Institutes of Health, Moffitt Skin Cancer SPORE (P50 CA168536). This work has been supported in part by the H. Lee Moffitt Cancer Center & Research Institute; an NCI designated

Conflicts of interest

The authors declare that they have no conflicts of interest.

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      It is well known as a neurotransmitter that reflected on metabolism and transport of the amino acid in the nervous system (Wiesinger, 2001). In mammalian cells, NO is produced from an oxidation reaction between L-arginine (L-arg) and oxygen, that has nicotinamide adenine dinucleotide phosphate as a co-substrate and is catalyzed by NOS (Yarlagadda et al. 2017). NO can be generated by three different isoforms of NOS: neuronal NOS (nNOS or nos1), inducible NOS (iNOS or nos2), and endothelial NOS (iNOS or nos3).

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