Investigating the role of obesogens affecting tumour microenvironment: the tributyltin-adipose tissue-prostate cancer cells triad

• Autor(a) principal: Casanova, César David Rodrigues
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/13611
• topic: Tecido Adiposo Periprostático; Cancro da Próstata; Desreguladores Endócrinos; Obesidade; Obesogénios; Secretoma; Tributilestanho; Domínio/Área Científica::Engenharia e Tecnologia::Bioquímica

Prostate cancer (PCa) is a leading cause of death worldwide and a major public health concern. Obesity, a well-established risk factor for PCa, has been shown an increased prevalence over the years. Focusing on the significant role of the tumour microenvironment in cancer physiopathology, recent studies have implicated the “obese” periprostatic adipose tissue (PPAT) in the onset and progression of PCa. In this condition, the PPAT secretion of adipokines, chemokines, and growth factors is affected, creating a pro-inflammatory environment, and providing alternative energy sources for tumour cells. Noteworthy, recent years have also shown that fat accumulation is more than a consequence of genetics, sedentarism or unhealthy eating behaviours, resulting from chronic exposure to endocrine-disrupting chemicals (EDCs), the so-called obesogens. The obesogen model tributyltin (TBT), a persistent aquatic contaminant once extensively used as a biocide in ship paints, induces adipocyte differentiation, lipid accumulation, and lipid droplet formation even with only a single day of exposure. The present dissertation hypothesizes that TBT can disrupt PPAT and its secretome, dysregulating the crosstalk with prostate cells and acting as a driving force in PCa. Conditioned media (CM) assays were performed by exposing neoplastic (PC3) and non-neoplastic (PNT1A) human prostate cells to the secretome of TBTtreated PPAT (PPAT-TBT-CM) and control (PPAT-CM) for 24 hours. Prostate cell viability, proliferation, apoptosis, and migration were analysed by MTT assay, Ki67 immunocytochemistry, caspase-3-like activity, and scratch assay, respectively. Moreover, to access metabolic changes, free fatty acids (FFAs), glucose consumption, and lactate production were evaluated by colorimetric assays. Thiobarbituric acid reactive substance (TBARS) assay and Griess assay were employed to access prostate cells’ lipid peroxidation levels and inflammatory response, respectively. Exposure to PPAT-TBT-CM resulted in increased viability, proliferation, and migration, accompanied by a reduction in the rate of apoptosis in both prostate cell lines. Considering the metabolic changes induced by PPAT-TBT-CM, PNT1A cells exhibited a significant increase in FFAs uptake and a decrease in glucose consumption, with no discernible differences found in lactate production. In contrast, in PC3 cells, PPATTBT-CM markedly increased FFAs and glucose uptake, and lactate production. Surprisingly, treatment with PPAT-TBT-CM decreased lipid peroxidation in both cell lines. Nitrite production upon exposure to PPAT-TBT-CM remained unchanged in PNT1A cells and showed a slight increase in PC3 cells. The present dissertation is the first report providing compelling evidence that TBT-induced dysregulation of PPAT can act as a driving force in the development of PCa. TBT exposure of PPAT promoted the cancer-like in both PNT1A and PC3 cells by a set of cancer cell fate and metabolic alterations. However, further studies are needed to characterize the TBT-dysregulated PPAT secretome and its underlying mechanisms of action in PCa. Thereby, the results obtained in this dissertation opened new perspectives of research to further explore the association of EDCs dysregulated PPAT with the development and progression of PCa.