Serum-derived extracellular vesicles mediate acquired multidrug resistance of MCF-7 breast cancer cells induced by chemotherapeutic drugs

Multidrug resistance (MDR) in tumor cells presents a significant challenge in cancer therapy. This study investigates the role of serum-derived extracellular vesicles (EVs) in mediating MDR during chemotherapeutic exposure. The findings indicate that short- or long-term co-incubation of doxorubicin (Dox)-pretreated serum derived EVs (EVs(S-PT)) caused drug-sensitive MCF-7 breast cancer cells to develop a MDR phenotype. In addition, serum EVs contain a high concentration of unglycosylated P-glycoprotein (P-gp). Chemotherapy treatment of tumor patients or exposure to chemotherapeutic drugs in vitro activates serum glycosyltransferases, inducing glycosylation of EVs P-gp and giving it drug-pumping activity. Furthermore, damage caused by Dox to the vascular endothelial barrier facilitates the crossing of serum EVs into the tumor microenvironment. These EVs are then taken up by tumor cells, providing them with access to a significant quantity of glycosylated P-gp proteins that possess transporter activity and the ability to evade degradation by the ubiquitin proteasome system. The results indicate that EVs(S-PT) transfers glycosylated P-gp across the damaged vascular endothelial barrier into MCF-7 cells and that these glycosylated P-gp remain intracellular for a long period of time, inducing MDR in the cells. Our study highlights a novel mechanism of acquired MDR and provides a potential avenue for therapeutic interventions targeting the serum EVs pathway in cancer therapy.