Small extracellular vesicle-mediated Hsp70 intercellular delivery enhances breast cancer adriamycin resistance

• Published in: Free radical biology & medicine Vol. 164; pp. 85 - 95
• Main Authors: Hu, Weizi, Xu, Zhi, Zhu, Shuyi, Sun, Wenbo, Wang, Xiumei, Tan, Chunli, Zhang, Yanyan, Zhang, Guangqin, Xu, Yong, Tang, Jinhai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2021
• Subjects: ADR resistance and breast cancer; Hsp70; Reprogramming energy metabolism; Small extracellular vesicles; Reprogramming energy metabolism; BCa; EVs; P-gp; Small extracellular vesicles; ADR resistance and breast cancer; Hsps; MTT; ADR; ECAR; LDH; Hsp70; PFK; shRNA; IC50; sEVs; PER; RT-qPCR; TEM; OCR
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.12.436

Adriamycin (ADR) resistance poses a significant challenge for successfully treating breast cancer (BCa). The mechanism underlying intrinsically acquisition of the resistance remains to be fully elucidated. Here, we describe that small extracellular vesicles (sEVs) mediated Hsp70 transfer is implicated in ADR resistance. The resistant cells derived sEVs were incubated with sensitive cells, thereby transmitting the resistant phenotype to the recipient cells. The internalization of the sEVs in the recipient cells and sEV-mediated Hsp70 transfer into mitochondria were examined by confocal microscope and transmission electron microscopy (TEM). Oxygen consumption rate (OCR) incorporated with extracellular acidification rate (ECAR) was quantified by Seahorse XF Analyzer. Mechanistically, sEVs transported Hsp70, leading to increased reactive oxygen species (ROS) and impaired mitochondria in the recipient cells, thereby inhibiting respiration but promoting glycolysis. The sEVs effect on the metabolism of the recipient cells was alleviated by silencing Hsp70 in sEVs donor cells. The aspect of sEV-Hsp70 on drug-resistant transmission was further validated by tumor zebrafish xenografts. The finding from this work suggests that sEV-mediated Hsp70 intercellular delivery enhances ADR resistance mainly through reprogramming the recipient cell energy metabolism. [Display omitted] •Adriamycin-resistant cells derived sEVs conferred the resistant phenotype to the sensitive cells.•sEVs intercellular transfer led to increasing cellular ROS and mitochondrial damage in the recipient cells.•sEVs from ADR-resistant cells confer the resistant phenotype to sensitive cells via Hsp70-mediated metabolic reprogramming.