Unraveling prostate cancer paradox - molecular, metabolic, and cytometric mechanisms in type 2 diabetes and metabolic syndrome

• Autor(a) principal: Sousa, André Miguel Pinto de
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.22/19912
• topic: Metabolic syndrome; Metabolism; Paradox; Prostate cancer; Type 2 diabetes mellitus

Prostate cancer (PCa) remains the third most common type of cancer in men worldwide in 2021. Despite its low death rate, the need for new therapies or prevention strategies is critical. The prostate carcinogenesis process is complex and multifactorial. Pca is caused by a variety of mutations and carcinogenic events that constitutes the disease’s multifactorial focus, capable of not only remodeling celular activity, but also modeling metabolic pathways to allow adaptation to the nutritional requirements of the tumor, creating a propitous microenvironment. Some risk factos have been linked to the development of PCa, including Metabolic Syndrome (MetS) and Type 2 diabetes Mellitus (T2DM). MetS is intrinsically related to PCa carcinogenic development, increasing it aggressiveness. On the other hand, T2DM has the opposite impact. Although in other carcinomas its Effect is similar to the MetS. Although these two metabolic disorders may share some development process, such as obesity, insulin resistance, na dyslipidemia, their influence on PCa prognosis appears to have na inverse Effect, which makes this a paradox. Unserstanding the phenomena behind this paradoxical behavior may lead to new concepts into the comprehension of the diseases, as well as to evaluate new therapeutical targets. Thus, the study aimed to evaluate the impacto f metabolic disorders in Pca’s aggressiveness state and metabolism. To accomplish that, two cell lines with antagonista expression of androgen receptors were submitted to several functional assays under metabolic disorders mimicry wre employed to evaluate the effect of metabolic disorders in PCa, such as viability, proliferation, migration, oxidative stress assays and cell death. Moreover, evaluation of metabolic pathways was carried to comprehend the Effect of those diseases in PCa development, through mitochondrial analyses with seahorse XFe24 analyzer, and by evaluating gene expression of some metabolic enzymes from glycolysis, gluconeogenesis, fatty acid synthesis, β-oxidation, cholesterol synthesis, and mitochondrial replication. Results pointed to a global reduction of tumoral features in both PCa cell lines under diabetic environment mimicry, notably proliferation, migration and cell survivor, indicating late apoptosis and necrosis. Additionally, mitochondrial evaluation showed almost null activity in T2DM environment, which were confirmed by gene expression. Moreover, genetic evaluation strengthened the paradox theory, once a general reduction of metabolic pathways was observed in T2DM. Inversely to theses observations, results in MetS showed a slight increase of PCa aggressiveness, enhancing features such as migration, and raising a propitious metabolic environment for PCa development. Overall, this study evidences a positive correlation between PCa and MetS, while a negative correlation was founded between PCa and T2DM, highlighting their opposite impacts in PCa aggressiveness, progression, and metabolic activity. It also reveals substantial evidence of this paradoxical behavior, pointing some possibel biological motives which may be the basis to it.