Contribution of sepiapterin reductase enzyme along melanoma development

• Grant number: 19/27517-0
• Support type: Regular Research Grants
• Duration: December 01, 2020 - November 30, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Fabiana Henriques Machado de Melo
• Grantee: Fabiana Henriques Machado de Melo
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The incidence of cutaneous melanoma has been increasing in recent years due to increased life expectancy and increased exposure to ultraviolet rays. Melanoma is an extremely aggressive cancer, with a high rate of metastasis and consequently high mortality. Late diagnosis, lack of tumor markers and inefficiency of available therapies are the main factors associated with high lethality. The high proliferative capacity of melanoma cells is associated with the alteration of numerous molecules, including growth factors, signaling proteins and cell cycle regulators. Altered cell cycle regulators include polyamines, aliphatic cations that play an important role in controlling proliferation, differentiation and apoptosis. The limiting enzyme in polyamine synthesis, ornithine decarboxylase, also exhibits altered expression and activity throughout carcinogenesis, contributing to tumor progression. Recently, it has been shown that the interaction of ornithine decarboxylase with the enzyme sepiapterine reductase increases the synthesis of polyamines, contributing to the growth of neuroblastoma cells, cancer that has the same embryonic origin as melanoma. Melanoma cells have already shown increased expression and activity of ornithine decarboxylase with consequently increased concentration of polyamines. Analysis of cutaneous melanoma samples from the TCGA (The Cancer Genome Atlas - https://cancergenome.nih.gov/) database showed a correlation between increased SPR expression and shorter patient survival. And data from our laboratory showed a progressive increase in sepiapterine reductase expression along melanoma progression, suggesting that this enzyme contributes to the development of the disease. In addition, mutated BRAF melanoma cells have a higher concentration of polyamines. The depletion of these polyamines makes these cells more sensitive to vemurafenib treatment. Previous data from our group also showed that mutated BRAF melanoma cells have increased SPR expression, which could contribute to increased polyamine concentration. Therefore, the aim of this study is to evaluate the role of sepiapterine reductase throughout the process of melanoma progression, its interaction with the polyamine pathway and whether sepiapterine reductase is involved in the acquisition of resistance to BRAF / MEK inhibitors. (AU)