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Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry

Melanoma is the most aggressive type of skin cancer due to its high capability of developing metastasis and acquiring chemoresistance. Altered redox homeostasis induced by increased reactive oxygen species is associated with melanomagenesis through modulation of redox signaling pathways. Dysfunction...

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Autores principales: de Melo, Fabiana Henriques Machado, Gonçalves, Diego Assis, de Sousa, Ricardo Xisto, Icimoto, Marcelo Yudi, Fernandes, Denise de Castro, Laurindo, Francisco R. M., Jasiulionis, Miriam Galvonas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430733/
https://www.ncbi.nlm.nih.gov/pubmed/34502464
http://dx.doi.org/10.3390/ijms22179556
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author de Melo, Fabiana Henriques Machado
Gonçalves, Diego Assis
de Sousa, Ricardo Xisto
Icimoto, Marcelo Yudi
Fernandes, Denise de Castro
Laurindo, Francisco R. M.
Jasiulionis, Miriam Galvonas
author_facet de Melo, Fabiana Henriques Machado
Gonçalves, Diego Assis
de Sousa, Ricardo Xisto
Icimoto, Marcelo Yudi
Fernandes, Denise de Castro
Laurindo, Francisco R. M.
Jasiulionis, Miriam Galvonas
author_sort de Melo, Fabiana Henriques Machado
collection PubMed
description Melanoma is the most aggressive type of skin cancer due to its high capability of developing metastasis and acquiring chemoresistance. 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 (O(2)(−•)) 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 O(2)(•) 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.
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spelling pubmed-84307332021-09-11 Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry de Melo, Fabiana Henriques Machado Gonçalves, Diego Assis de Sousa, Ricardo Xisto Icimoto, Marcelo Yudi Fernandes, Denise de Castro Laurindo, Francisco R. M. Jasiulionis, Miriam Galvonas Int J Mol Sci Article Melanoma is the most aggressive type of skin cancer due to its high capability of developing metastasis and acquiring chemoresistance. 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 (O(2)(−•)) 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 O(2)(•) 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. MDPI 2021-09-03 /pmc/articles/PMC8430733/ /pubmed/34502464 http://dx.doi.org/10.3390/ijms22179556 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
de Melo, Fabiana Henriques Machado
Gonçalves, Diego Assis
de Sousa, Ricardo Xisto
Icimoto, Marcelo Yudi
Fernandes, Denise de Castro
Laurindo, Francisco R. M.
Jasiulionis, Miriam Galvonas
Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title_full Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title_fullStr Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title_full_unstemmed Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title_short Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry
title_sort metastatic melanoma progression is associated with endothelial nitric oxide synthase uncoupling induced by loss of enos:bh4 stoichiometry
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430733/
https://www.ncbi.nlm.nih.gov/pubmed/34502464
http://dx.doi.org/10.3390/ijms22179556
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