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

Autor(es)

Machado de Melo, Fabiana Henriques ^{[1, 2]} ; Goncalves, Diego Assis ^{[3, 4]} ; de Sousa, Ricardo Xisto ^[5] ; Icimoto, Marcelo Yudi ^[6] ; Fernandes, Denise de Castro ^[7] ; Laurindo, Francisco R. M. ^[7] ; Jasiulionis, Miriam Galvonas ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508060 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Pharmacol Dept, BR-05508090 Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Microimunoparasitol Dept, BR-05508090 Sao Paulo - Brazil

^[4] Univ Fed Juiz de Fora, Parasitol Dept, Microbiol & Immunol, BR-36036900 Juiz De Fora - Brazil

^[5] Santa Casa de Sao Paulo Sch Med Sci, Dept Physiol Sci, BR-01221020 Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo, Biophys Dept, BR-05508090 Sao Paulo - Brazil

^[7] Univ Sao Paulo, Heart Inst InCor, Vasc Biol Lab, Sch Med, BR-05508060 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 17 SEP 2021.
• Citações Web of Science: 0

Resumo

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(-center dot)) 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(center dot) 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. (AU)

• Processo FAPESP: 14/13663-0 - Integração de dados de expressão de genes e microRNAs, metiloma e hidroximetiloma de diferentes etapas da progressão do melanoma.
• Beneficiário: Miriam Galvonas Jasiulionis
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/10695-7 - Avaliação da expressão e atividade das enzimas que participam da síntese da tetrahidrobiopterina e dos níveis de tetrahidrobipterina ao longo da gênese do melanoma
• Beneficiário: Ricardo Coleto Xisto de Sousa
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 17/04352-0 - Contribuição da interação entre a caveolina-1 e as enzimas GTP ciclohidrolase I e sintase de óxido nítrico ao longo da progressão do melanoma
• Beneficiário: Fabiana Henriques Machado de Melo
• Linha de fomento: Auxílio à Pesquisa - Regular