Endocrine disruptors, obesity, and prostate cancer: a metabolic perspective

• Autor(a) principal: Serra, Catarina Maria Dias
• 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/10400.6/11264
• topic: Cancro da Próstata; Disruptores Endócrinos; Metabolismo; Obesidade; Tributilestanho (Tbt); Domínio/Área Científica::Engenharia e Tecnologia::Bioquímica

Prostate cancer (PCa) is one of the most diagnosed cancer in men and represents the fifth leading cause of cancer death. In the current state the risk factors for PCa include endogenous factors, namely aging, ethnicity, hormones, family history, genetic factors and oxidative stress, or exogenous, such as diet, obesity, physical inactivity, lifestyle and environmental factors. It was recently reported that extrinsic factors contribute more than 99.9% to the risk of PCa development. Extrinsic factors like lifestyle, dietary factors or environmental factors like UV radiation, carcinogens and pesticide exposure have been implicated in the etiology of PCa. Endocrine-disrupting chemicals (EDCs) are a group of compounds that can interfere with the endocrine system, which includes alterations in hormone production, secretion, transport, and/or action. There is a subset of EDCs that alter the metabolism to benefit the storage of lipids, leading to a predisposition to obesity, called obesogens. Tributyltin (TBT) is an EDC widely used and dispersed in the environment, which has obesogenic and androgenic properties. Metabolism is defined as a set of diverse biochemical processes in living organisms, being responsible for the use of nutrients and energy production in humans and other organisms. The metabolic reprogramming is a well-known hallmark of cancer and several studies showed that PCa cells have the ability of reprogramming metabolism to survive and metastasize. However, the metabolic deregulation induced by obesity or obesogens, namely TBT, in metabolism of PCa cells remains unknown. Thus, the aim of this dissertation was to evaluate the effect of TBT regulating the glycolytic and lipid metabolism of PCa cells, and the influence of obesogenic conditions on TBT actions. Therefore, non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cells were stimulated with TBT (10 or 100 nM), low-density lipoprotein (LDL) and/or 5a-dihydrotestosterone (DHT) for 48 hours. Then, glucose consumption, lactate production and the enzymatic activity of lactate dehydrogenase (LDH) were determined through spectrophotometric analysis. Protein expression of target regulators of glycolytic and lipid metabolism was analyzed by Western blot (WB). Lipid droplets (LD) quantification was determined by staining with Oil Red-O. The present results showed that the treatment with 100 nM TBT stimulated the glycolytic flux by enhancing glucose consumption, lactate production and LDH activity in androgen-sensitive LNCaP cells. These results were underpinned by the increased expression of the glycolytic enzyme phosphofructokinase-1 (PFK1) and monocarboxylate transporter 4 (MCT4). In addition, TBT treatment also stimulated lipid synthesis by increasing the expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) proteins in PNT1A and LNCaP cells, which was supported by the increase in lipid content. This increase in LDs was also observed in LNCaP cells stimulated with 10 nM TBT. This effect was suppressed by the availability of LDL-cholesterol. Altogether, the present findings demonstrate that TBT contributes to the metabolic rewiring of PCa cells, stimulating glycolytic and lipid metabolism and contributing for PCa development and progression. In addition, TBT in the presence of LDL disrupts lipid metabolism inducing the usage of lipids, which may contribute to the progression of cancer.