Extracellular Vesicles Released From Prostate Cancer Cells Confer Pro‐Tumor Properties to Adipocytes by Stimulating Lipolysis

There is consistent evidence of an association between obesity and the risk of prostate cancer (PCa). A crosstalk between PCa and adipocytes has been highlighted; however, the role of extracellular vesicles (EVs) in this communication still needs to be elucidated. Herein, we demonstrated that PCa EVs can trigger lipolysis in 3T3-L1 adipose cells, by downregulating G0/G1 switch protein 2 (G0S2), inducing adipose triglyceride lipase (ATGL) expression and activating the cyclic AMP (cAMP)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) signaling pathway. Interestingly, we showed that the free fatty acids (FFAs) released from the EV-treated adipocytes could increase PCa cell proliferation and clonogenic ability. Moreover, they promoted tumor cell migration and invasion, while parallelly reducing the induction of anoikis. Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype.