Contribution of the interaction between caveolin-1 and the enzymes GTP cyclohydrolase I and nitric oxide synthase along melanoma progression

• Grant number: 17/04352-0
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2017 - June 30, 2019
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Fabiana Henriques Machado de Melo
• Grantee: Fabiana Henriques Machado de Melo
• Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil

Abstract

The incidence of melanoma has been increasing in recent years due to increased life expectancy and increased exposure to ultraviolet rays. Melanoma is an extremely aggressive cancer, showing high rate of metastasis and consequently a high mortality. Late diagnosis, lack of tumor markers and inefficiency of available therapies are the main factors associated with high lethality. One of the mechanisms involved in the carcinogenesis of melanoma is the reactive oxygen species increase, among them the superoxide anion, which is produced by dysfunctional nitric oxide synthase (NOS). The superoxide anion activates signaling pathways associated with cell survival, increased proliferation and resistance to apoptosis, contributing to tumor development. The activity of NOS in endothelial cells is regulated by integrated mechanisms, including the bioavailability of the tetrahydrobiopterin cofactor (BH4) and the interaction with caveolin-1, a protein located in supramolecular structures of the plasma membrane called caveolas. The activity of the limiting enzyme in the synthesis of BH4, the GTPCHI, is also modulated by binding to caveolin-1 in endothelial cells. Data from our group show that NOS dysfunction due to decreased levels of BH4 contributes to the survival of metastatic melanoma cells, but other groups have shown that in other cancers, it is the increase in BH4 levels that favors carcinogenesis. The expression of caveolin-1 is altered in several cancers, contributing positively or negatively to the different stages of tumor progression, which seems to be related to differential interaction with other proteins. In tumor cells, the interaction between NOS and GTPCHI with caveolin-1 and what its contribution to tumorigenesis has not been described. Based on this information, the objective of this work is to evaluate at different stages of melanoma progression, whether there is interaction between these proteins and what the contribution of these connections in the development of melanoma. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MONTOR, WAGNER RICARDO; SILVA ESCARTIN SALAS, ANDREI RONALDO OLIVEIRA; MACHADO DE MELO, FABIANA HENRIQUES. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Molecular Cancer, v. 17, FEB 19 2018. (17/04352-0)

MACHADO DE MELO, FABIANA HENRIQUES; OLIVEIRA, JULIA SALLES; BRESSANI SARTORELLI, VIVIANI OLIVASTRO; MONTOR, WAGNER RICARDO. Cancer Chemoprevention: Classic and Epigenetic Mechanisms Inhibiting Tumorigenesis. What Have We Learned So Far?. FRONTIERS IN ONCOLOGY, v. 8, DEC 21 2018. (17/17986-7, 17/04352-0)

MACHADO DE MELO, FABIANA HENRIQUES; GONCALVES, 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. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 17, SEP 2021. (14/13663-0, 17/10695-7, 17/04352-0)

GONCALVES, DIEGO ASSIS; XISTO, RICARDO; GONCALVES, JESSICA DOMINGUES; DA SILVA, DOUGLAS BACETI; MOURA SOARES, JAQUELINE PEREIRA; ICIMOTO, MARCELO YUDI; SANT'ANNA, CARLA; GIMENEZ, MARCELA; DE ANGELIS, RADA; LLESUY, SUSANA; et al. Imbalance between nitric oxide and superoxide anion induced by uncoupled nitric oxide synthase contributes to human melanoma development. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v. 115, OCT 2019. (17/10695-7, 14/13663-0, 17/04352-0)