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Association between PAF-mediated signaling and its receptor and autophagy in human melanoma cell lines after hypoxia and reoxygenation cycles and nutrient deprivation

Grant number: 13/22055-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): January 01, 2014
Effective date (End): December 31, 2014
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Roger Chammas
Grantee:Mayara Dauria Jacomassi
Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Melanoma, as other solid tumors, is set up of a heterogeneous mass of cells. The distribution of oxygen and nutrients through the blood vessels occurs unevenly. Once there is an excessive cell proliferation, some areas of the tumor go through nutrient deprivation and hypoxia. In both contexts cells undergoing apoptosis and necrosis can still be activating the autophagy. This catabolic process is important for the maintenance of cellular homeostasis through the housekeeping and survival. As this occurs in situations frequently found in tumors, the interest of relating this mechanism with the process of tumor progression has increased in recent years. Autophagy can be amplified by reperfusion of areas that were under hypoxia and some studies suggest that tumor cells undergoing this process are exactly those that resist treatment. In addition to this amplification, the reoxygenation could lead to the production of molecule PAF and its derivatives by oxidation of lipids of the cell membrane. PAF isn't stored in cells, and its synthesis is dependent of cell activation by various stimuli, such as growth factors, radiation, oxidative stress, and is secreted by different cell types such as endothelial cells, inflammatory cells, stromal cells and tumor cells, as well melanoma. As there seems to be a relationship between PAF receptor and protection to cell damage, we want to evaluate the possible relationship between siganling of PAF and its receptor, PAFR and autophagy in human melanoma cell line using hypoxia and reoxygenation cycles and nutrient deprivation. Thus, the lineage SKmel37 will be exposed to hypoxia followed by reoxygenation and nutrient deprivation, in order to observe the expression of PAFR in protein levels, comparing this expression with controls. Furthermore, autophagy will also be analyzed in the same experimental model. Once determined the best conditions for visualize these events the relationship between autophagy and PAFR will be examined using an inhibitor of autophagy, 3-methyladenine, and PAFR antagonist, WEB 2086. If, in fact, there is an increased expression of PAFR in this model, as well as increased activation of autophagy, and if there is a relationship between them, using PAFR antagonist may be a good therapeutic target to improve the efficiency of conventional treatment with chemotherapy.