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Study of the mechanisms of internalization and action of peptides from transcription factor BRN2 and of natural compounds in Melanoma and Breast Cancer

Grant number: 22/06400-0
Support Opportunities:Regular Research Grants
Duration: February 01, 2023 - January 31, 2025
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Denise Costa Arruda
Grantee:Denise Costa Arruda
Host Institution: Pró-Reitoria Acadêmica. Universidade de Mogi das Cruzes (UMC). Campus da Sede Mogi das Cruzes. Mogi das Cruzes , SP, Brazil
Associated researchers:Daniela Leite Jabes ; Dayane Batista Tada ; Fabiano Bezerra Menegidio ; Fernanda Ramos Gadelha ; Luiz Roberto Nunes ; Tiago Rodrigues

Abstract

Melanoma is formed from the malignant transformation of melanocytes. Despite the low incidence in the population, it is considered the most serious type of Skin Cancer, due to its high rate of metastases. Contrastingly, Breast Cancer is one of the most prevalent types of cancer in the world. Peptides derived from the DNA-binding domain (POU domain) of the transcription factor BRN2 have shown important effects in Melanoma cells,such as induction of cell death and cell cycle arrest, inhibition of migration and invasion, and reduction of pulmonary nodules in treated animals. Furthermore, we observed by confocal microscopy experiments using biotinylated peptides bind to the nucleus and actin of treated cells. However, it is not yet known whether the peptide binds to the DNA binding domain of the BRN2 protein, to another nonspecific sequence, or to nuclear proteins. Some natural compounds have also been tested in our laboratory and have shown important antitumor effects, such as induction of apoptosis, autophagy, and reactive oxygen species in Melanoma cells, as well as antitumor effects in vivo. The aim of this project is to determine whether the peptides interfere in the modulation of genes regulated by BRN2 using Western Blotting, real-time PCR, and RNAseq techniques. We will determine the mechanisms of peptide internalization using internalization inhibitors and confocal microscopy. We will also determine the cellular ligands of biotinylated BRN2-derived peptides using the Electrophoretic Mobility Shift Assay to determine DNA binding, and use a streptavidin-agarose column and mass spectrometry to observe binding to actin. Additionally, we will study the peptides and natural compounds in a Breast Cancer model, using murine and human Breast Cancer strains for in vitro experiments. We will investigate the type of cell death induced by the peptides, mechanism of action in these cells, investigate inhibition of migration and invasion, and interference in the cell cycle. Finally, we will test these compounds using an in vivo Breast Cancer model.Studies with new natural or synthetic compounds with antitumor activity in vitro and in vivo in Breast Cancer and Melanoma are important for the development of new products to be used in therapeutics for cancer treatment. (AU)

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