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Altered redox homeostasis induced by increased reactive oxygen species is associated with melanomagenesis through modulation of redox signaling pathways. Dysfunctional endothelial nitric oxide synthase (eNOS) produces superoxide anion (O2\u2212\u2022) and contributes to the establishment of a pro-oxidant environment in melanoma. Although decreased tetrahydrobiopterin (BH4) bioavailability is associated with eNOS uncoupling in endothelial and human melanoma cells, in the present work we show that eNOS uncoupling in metastatic melanoma cells expressing the genes from de novo biopterin synthesis pathway Gch1, Pts, and Spr, and high BH4 concentration and BH4:BH2 ratio. Western blot analysis showed increased expression of Nos3, altering the stoichiometry balance between eNOS and BH4, contributing to NOS uncoupling. Both treatment with L-sepiapterin and eNOS downregulation induced increased nitric oxide (NO) and decreased O2\u2022 levels, triggering NOS coupling and reducing cell growth and resistance to anoikis and dacarbazine chemotherapy. Moreover, restoration of eNOS activity impaired tumor growth in vivo. Finally, NOS3 expression was found to be increased in human metastatic melanoma samples compared with the primary site. eNOS dysfunction may be an important mechanism supporting metastatic melanoma growth and hence a potential target for therapy.<\/jats:p>","DOI":"10.3390\/ijms22179556","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T13:09:25Z","timestamp":1630933765000},"page":"9556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry"],"prefix":"10.3390","volume":"22","author":[{"given":"Fabiana Henriques Machado de","family":"Melo","sequence":"first","affiliation":[{"name":"Pharmacology Department, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"},{"name":"Department of Pharmacology, Institute of Biomedical Science, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-060, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7351-3558","authenticated-orcid":false,"given":"Diego Assis","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Micro-Imuno-Parasitology Department, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"},{"name":"Parasitology Department, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Xisto de","family":"Sousa","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Santa Casa de S\u00e3o Paulo School of Medical Sciences, S\u00e3o Paulo 01221-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0746-5279","authenticated-orcid":false,"given":"Marcelo Yudi","family":"Icimoto","sequence":"additional","affiliation":[{"name":"Biophysics Department, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise de Castro","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Vascular Biology Laboratory, Heart Institute (InCor), University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo 05508-060, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco R. M.","family":"Laurindo","sequence":"additional","affiliation":[{"name":"Vascular Biology Laboratory, Heart Institute (InCor), University of S\u00e3o Paulo School of Medicine, S\u00e3o Paulo 05508-060, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam Galvonas","family":"Jasiulionis","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1126\/science.1253735","article-title":"The Melanoma Revolution: From UV Carcinogenesis to a New Era in Therapeutics","volume":"346","author":"Lo","year":"2014","journal-title":"Science"},{"key":"ref_2","first-page":"1005","article-title":"Melanoma: Epidemiology, Risk Factors, Pathogenesis, Diagnosis and Classification","volume":"28","author":"Rastrelli","year":"2014","journal-title":"In Vivo"},{"key":"ref_3","first-page":"73","article-title":"Recent Advances in the Treatment of Melanoma","volume":"89","author":"Curti","year":"2021","journal-title":"N. 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