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Effects of docosahexaenoic acid on the modulation of cell cycle and cell death at prostatic carcinogenesis

Grant number: 19/15109-4
Support type:Scholarships in Brazil - Master
Effective date (Start): November 01, 2019
Effective date (End): January 26, 2020
Field of knowledge:Biological Sciences - Morphology - Histology
Principal Investigator:Rejane Maira Góes
Grantee:Alana Della Torre da Silva
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil

Abstract

Prostate cancer (PCa) is one of the five leading causes of death in male individuals on the world stage and a serious public health problem. Currently, it is know that diet and particularly that high lipid intake, as well as its nature, are implicated in the genesis of this disease. The marine omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were considered protective agents against CaP due to their anti-proliferative and antitumor properties, however, recent studies highlighted that higher consumption or high serum concentrations of these PUFAs are associate with increase risk of PCa development. Therefore, this project aims to evaluate the effects of DHA and EPA at different stages of CaP progression, focusing on the cell cycle modulation and regulated cell death processes in in vivo and in vitro models. For this, transgenic mice for prostate adenocarcinoma (TRAMP) will be treated with a diet rich in DHA + EPA or standard and the biometric parameters, lipid profile and serum testosterone and estradiol concentration will be evaluated, as well as the histopathology of the ventral prostate regarding the incidence of the pre-malignant lesions, well differentiated carcinoma and undifferentiated adenocarcinoma. In vitro studies will be performed using PNT1A (benign) and 22rv1 (androgen-responsive) cell lines. For these lines, dose-response assay will be performed with MTS to determine which concentration has antiproliferative effect, followed by cycle and cell death analysis by flow cytometry. In both in vivo and in vitro assays will be evaluate the cell proliferation and survivor by Western blotting and immunohistochemistry for phospho-AKT, mTOR, phospho-PTEN, ERK 1/2 and phospho-Histone H3, as well as the cell death patterns by the expression of activated caspase-3 (apoptosis), phospho-MLKL (necroptosis), cleaved gasdermin D (pyroptose) and LC3B (autophagy), which will be confirmed by transmission electron microscopy. The results obtained will better understand the pathways that PUFAs can affect cell proliferation and death, which may support new therapeutic strategies. (AU)