Imbalance between nitric oxide and superoxide anion induced by uncoupled nitric oxide synthase contributes to human melanoma development

Author(s):Show less -

Goncalves, Diego Assis ^{[1, 2]} ; Xisto, Ricardo ^[3] ; Goncalves, Jessica Domingues ^[1] ; da Silva, Douglas Baceti ^[3] ; Moura Soares, Jaqueline Pereira ^[3] ; Icimoto, Marcelo Yudi ^[4] ; Sant'Anna, Carla ^[3] ; Gimenez, Marcela ^[3] ; de Angelis, Rada ^[3] ; Llesuy, Susana ^[5] ; Fernandes, Denise C. ^[6] ; Laurindo, Francisco ^[6] ; Jasiulionis, Miriam Galvonas ^[1] ; Machado de Melo, Fabiana Henriques ^[3]

Affiliation

^[1] Univ Fed Sao Paulo, Pharmacol Dept, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Microimunoparasitol, Sao Paulo - Brazil

^[3] Santa Casa Sao Paulo Sch Med Sci, Dept Physiol Sci, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Biophys Dept, Sao Paulo - Brazil

^[5] Univ Buenos Aires, Dept Gen & Inorgan Chem, Buenos Aires, DF - Argentina

^[6] Univ Sao Paulo Sch Med, Heart Inst InCor, Vasc Biol Lab, Sao Paulo - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; v. 115, OCT 2019.
• Web of Science Citations: 1

Abstract

Melanoma is the most aggressive type of cutaneous tumors due to its metastatic potential and high mortality. Increased levels of reactive oxygen species, including superoxide anion (O-2(center dot-)), and the consequent installation of a pro-oxidant environment are associated with melanoma development. The enzyme nitric oxide synthase (NOS), responsible for the production of nitric oxide (NO), when uncoupled is as a source of O-2(center dot-), for example by the absence of its cofactor tetrahydrobiopterin (BH4). Western blot analysis showed increased expression of endothelial and inducible NOS in human melanoma cells, altering the stoichiometry between NOS levels and BH4 concentration and together with decreased BH4:BH2 ratio are contributing to NOS uncoupling. The treatment of melanoma cells with exogenous BH4 increased NO concentration and decreased O-2(center dot-) levels, leading to NOS coupling, which in turn reduced cell viability, cell proliferation and the ability of melanoma cells to form melanoma spheroids. Moreover, BH4 level restoration rendered melanoma cells more sensitive to apoptosis, demonstrating the role of dysfunctional NOS in melanoma genesis. (AU)

• FAPESP's process: 17/04352-0 - Contribution of the interaction between caveolin-1 and the enzymes GTP cyclohydrolase I and nitric oxide synthase along melanoma progression
• Grantee: Fabiana Henriques Machado de Melo
• Support type: Regular Research Grants
• FAPESP's process: 14/13663-0 - Integrating gene and microRNA expression, methylome and hidroxymethylome data from different phases of melanoma progression.
• Grantee: Miriam Galvonas Jasiulionis
• Support type: Regular Research Grants
• FAPESP's process: 17/10695-7 - Analysis of expression and activity of tetrahydrobiopterin enzymes pathway and tetrahydrobiopterin levels along melanoma development
• Grantee: Ricardo Coleto Xisto de Sousa
• Support type: Scholarships in Brazil - Scientific Initiation