Exosomes play an important role in the process of psoralen reverse multidrug resistance of breast cancer.

Xiaohong Wang,Chengfeng Xu,Zhongming Jia,Zhenlin Yang,Leitao Sun,Yuzhen Cui,Yitong Hua,Yong Han,Jianli Dong,Kai Cheng

doi:10.1186/s13046-016-0468-y

Abstract

BackgroundRelease of exosomes have been shown to play critical roles in drug resistance by delivering cargo. Targeting the transfer of exosomes from resistant cells to sensitive cells may be an approach to overcome some cases of drug resistance.MethodIn this study, we investigated the potential role of exosomes in the process of psoralen reverse multidrug resistance of MCF-7/ADR cells. Exosomes were isolated by differential centrifugation of culture media from MCF-7/ADR cells (ADR/exo) and MCF-7 parental cells (S/exo). Exosomes were characterized by morphology, exosomal markers and size distribution. The ability of ADR/exo to transfer multidrug resistance was assessed by MTT and real-time quantitative PCR. The different formation and secretion of exosomes were detected by immunofluorescence and transmission electron microscopy. Then we performed comparative transcriptomic analysis using RNA-Seq technology and real-time quantitative PCR to better understand the gene expression regulation in exosmes formation and release after psoralen treatment.ResultsOur data showed that exosomes derived from MCF-7/ADR cells were able to promote active sequestration of drugs and could induce a drug resistance phenotype by transferring drug-resistance-related gene MDR-1 and P-glycoprotein protein. Psoralen could reduce the formation and secretion of exosomes to overcome drug resistance. There were 21 differentially expressed genes. Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to PPAR and P53 signaling pathways which were related to exosomes formation, secretion and cargo sorting.ConclusionsPsoralen can affect the exosomes and induce the reduction of resistance transmission via exosomes might through PPAR and P53 signaling pathways, which might provide a novel strategy for breast cancer resistance to chemotherapy in the future.

Highlights

Release of exosomes have been shown to play critical roles in drug resistance by delivering cargo
Our data showed that exosomes derived from MCF-7/ADR cells were able to promote active sequestration of drugs and could induce a drug resistance phenotype by transferring drug-resistance-related gene multidrug resistance (MDR)-1 and Pglycoprotein protein
Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to PPAR and P53 signaling pathways which were related to exosomes formation, secretion and cargo sorting

Summary

Introduction

Release of exosomes have been shown to play critical roles in drug resistance by delivering cargo. Chemotherapy plays an important role against breast cancer, but its development is mainly restricted by drug resistance. It has been demonstrated that the release of exosomes maybe a mechanism in drug resistance in cancer cells by transferring drug transporter nucleic acid and proteins and/or accumulating anticancer drugs [6]. Such phenomenon was observed in several tumour models, including ovarian cancer [7], prostate cancer [8, 9] and osteosarcoma [10]. Reducing formation and secretion of exosomes may be a novel therapeutic strategy for adjuvant cancer treatment by restoring drug sensitivity in breast cancer [4, 13, 14]

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Conclusion