Papel das vesículas extracelulares derivadas do tecido adiposo sobre o balanço redox e malignidade de células de tumor de mama MDA-MB-231

Abstract

Obesity is a condition characterized by chronic low-grade inflammation and metabolic dysregulation. Additionally, during obesity, there is an increase in the trafficking of extracellular vesicles (EVs) and the maintenance of an oxidative stress state, resulting from adipose tissue (AT) accumulation. Both EVs and reactive oxygen species (ROS) can extensively modulate signaling and metabolic pathways in tumor cells. In this context, the present study aimed to understand the modulation of ROS production and its importance in the metabolic reprogramming and functional processes of MDA-MB-231 breast tumor cells stimulated with EVs derived from the subcutaneous AT of individuals with obesity (OB-EVs) and eutrophic individuals (EUT-EVs). We hypothesized that OB-EVs induce an increase in ROS production in tumor cells, modulating their energy metabolism and enhancing breast tumor malignancy. Our results demonstrated that OB-EVs induced a 10% increase in total ROS production and a 50% increase in mitochondrial ROS (mtROS) production compared to the untreated group. In the presence of MitoTempo (MT), a mitochondrial ROS scavenger, a 25% reduction in total ROS production was observed. Unexpectedly, in the presence of DPI, an inhibitor of NADPH oxidases (NOX), total ROS levels were maintained while mitochondrial ROS production decreased by 30%. Furthermore, OB-EVs were found to enhance migratory capacity in a ROS-dependent manner, along with increased AKT phosphorylation and stabilization of the transcription factor HIF-1α, which was inhibited in the presence of MT. Additionally, OB-EVs induced an increase in the activity of the pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase and a trend toward increased ATP content, while reducing the activity of the glycolytic enzyme pyruvate kinase. These effects were reduced in the presence of MT, together with an increase in the lactate content. Altogether, our data indicate that OB-EVs promote increased ROS production, particularly of mitochondrial origin, resulting in metabolic remodeling that appears to favor an oxidative profile, associated with increased migratory capacity. In the presence of MT, these effects were inhibited, shifting toward a more glycolytic profile. Thus, this study highlights the impact of EVs derived from obese AT on the metabolic reprogramming and malignancy of MDA-MB-231 breast tumor cells, through the lens of redox balance.