Docosahexaenoic acid is able to modulate autophagy in prostate Cancer in TRAMP rats?

• Grant number: 22/08339-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): September 01, 2022
• Effective date (End): November 30, 2024
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Rejane Maira Góes
• Grantee: Giulia Panula Mazarini
• Host 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

The modulation of autophagy may be an adjuvant in therapies for prostate cancer treatment. However, its role in cancer is complex and context-dependent, as autophagy can acts as a tumor suppressor in the early stages of tumor development or favors tumor progression in established or advanced tumors. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that affects apoptosis in prostate tumor cells, but its effect on autophagy is still not well understood. In this study we will examine: (1) whether activation of the autophagic pathway occurs during tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP); (2) whether blockage of autophagy by treatment with the autophagy inhibitor hydroxychloroquine affects tumor progression and severity in this model and (3) whether a diet enriched with DHA is able to modulate the autophagic response in this type of cancer and affect tumor progression. TRAMP mice will be fed from the 8th to the 12th (initial phase - eC and eD groups) or from the 8th. the 20th week (advanced stage of tumor progression - groups lC, lD), with standard chow or with chow enriched with DHA, without additional treatment, already obtained from a previous experiment. Groups subject to the two diets from the 8th to the 16th week (intermediate stage of tumor progression) without additional treatment (iC, iD) or treated from the 12th to 16 weeks with hydroxychloroquine (iH, iDH) will also be used. The prostates will be histologically processed and analyzed for the frequency of areas containing normal epithelium, high and low-grade prostatic intraepithelial neoplasia, and differentiated tumor. Immunohistochemistry will be performed for markers of autophagosomes (LC3B), necroptosis (pMLKL), pyroptosis (cleaved gasdermin D), and the TUNEL method (apoptosis). The LC3B immunostaining will be quantified by densitometry for each type of area/lesion and in the peripheral, intermediate, and necrotic regions of the advanced tumor. The activation of the main autophagy-modulating pathways (mTOR1, PI3K/AKT, and AMPK) will also be evaluated by Western Blotting. In addition to elucidating the role of autophagy in different stages of tumor progression in TRAMP, this study will clarify whether DHA and hydroxychloroquine treatment differentially modulate this pathway at different stages of PCa.(AU)