ROLE OF LEPTIN PRESENT IN EXTRACELLULAR VESICLES RELEASED BY OBESE ADIPOSE TISSUE ON MDA-MB-231 CELLS

Introduction: Leptin is considered a link between obesity and breast cancer. It is released by the adipose tissue (AT) in a soluble form or within extracellular vesicles (EVs). Considering that EVs can modulate the microenvironment and promote cancer cell malignancy, the main hypothesis of the present study is that EVs connect the AT to breast tumor cells through the delivery of leptin, whose levels are increased within the obese AT, thus triggering metabolic rearrangement towards aggressiveness. Aim: Evaluate the effects of leptin present in EVs released by obese AT upon the MDA-MB-231 breast cancer cell line. Methodology: EVs were obtained from subcutaneous AT from eutrophic and obese individuals submitted to plastic and bariatric surgery, respectively (CAAE: 36880914.0.0000.5259; CAAE: 56302121.2.0000.5259). MDA-MB-231 cells were stimulated with 20% (v/v) of EVs released from obese (OB EVs) or eutrophic AT (EUT EVs) and 100 nM Leptin, both in the presence or absence of 250 ng/mL of the Super Human Leptin Antagonist. Migration was assessed by wound healing, invasion through the transwell coated with a matrigel-like and STAT3 by western blotting. L-lactate, the activity of glucose-6-phosphate dehydrogenase (G6PDH), and pyruvate kinase (PK) were accessed by colorimetric kits (MAK329, MAK190, MAK015, and MAK071, respectively). Mitochondrial biogenesis was investigated with immunofluorescence. One-way ANOVA with Bonferroni post-test was performed. Statistically significant results were considered for p values <0.05. Results: The leptin in OB EVs enhanced migration, invasion, STAT3 phosphorylation, and mitochondrial biogenesis in MDA-MB-231. Furthermore, OB EVs reduced PK activity and decreased lactate content while increasing the activity of G6PDH, a step rate-limiting enzyme in the pentose-phosphate pathway. Conclusion: Leptin present in EVs released by obese AT increases the malignancy of MDA-MB-231.