Contribution of the interaction between Caveolin-1 and the enzyme GTP-cyclohydrola...
| Grant number: | 17/04352-0 |
| Support type: | Regular Research Grants |
| Duration: | July 01, 2017 - June 30, 2019 |
| Field of knowledge: | Biological Sciences - Morphology |
| Principal Investigator: | Fabiana Henriques Machado de Melo |
| Grantee: | Fabiana Henriques Machado de Melo |
| Home 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)