Contribuições metabólicas de vesículas extracelulares liberadas por pré-adipócitos obesos sob células tumorais de mama MDA-MB-231

Abstract

Obesity is a known risk factor for breast cancer, but the mechanisms behind this relationship remain unknown. In this scenario, despite being neglected, pre-adipocytes play an important role. This study aimed to develop an in vitro model to obtain extracellular vesicles released by obese (VE PAD OB) or eutrophic (VE PAD EUT) preadipocytes and then evaluate their functional and metabolic effects on MDA breast tumor cells. -MB-231. Initially, human pre-adipocytes of primary lineage were exposed to the secretome from cultured subcutaneous adipose tissue explants from obese or eutrophic individuals from abdominoplasty and mammoplasty surgeries performed at the Federal Hospital of Ipanema (CAAE:36880914.0.0000.5259). After the education process, preadipocyte vesicles were isolated and administered to MDA-MB-231 cells in the presence or absence of 2-deoxy-d-glucose (2-DG), an inhibitor of glycolytic metabolism, and Etomoxir ( ETO), inhibitor of fatty acid oxidation. The results indicated that VE PAD OB and VE PAD EUT induce specific and specific metabolic responses in MDA-MB-231 cells. VE PAD OB increased the migratory capacity by 3-fold in MDA-MB-231 cells compared to untreated cells, and 1.8 times compared to cells treated with VE PAD EUT. Interestingly, we reported the reversal of this increase in the presence of ETO, with a 2.3-fold decrease in the group treated with VE PAD OB and 1.5 times in the group treated with VE PAD EUT, highlighting the importance of fatty acid oxidation for the increased migratory capacity of these cells, especially that mediated by VE PAD OB. It was also seen that only VE PAD EUT increases total L-Lactate levels in MDA-MB-231 cells, indicating that the metabolic profile induced by VE PAD EUT would be more glycolytic. In the presence of ETO, VE PAD OB increased L-Lactate levels and prevented Glucose-6-Phosphate Dehydrogenase (G6PDH) activity. Our findings demonstrate that in vitro conditioning of preadipocytes is a functional tool to mimic the AT microenvironment under different physiological conditions. Furthermore, our results indicate that VE PAD EUT favors glycolytic metabolism while VE PAD OB favors oxidative metabolism. Furthermore, we report that VE PAD EUT and VE PAD OB increase migratory capacity in different proportions and that this is due to changes in different metabolic pathways that occur in MDA-MB 231 cells in both conditions.