β-Elemene Reverses Chemoresistance of Breast Cancer Cells by Reducing Resistance Transmission via Exosomes

Abstract

Background: Currently, exosomes that act as mediators of intercellular communication are being researched extensively. Our previous studies confirmed that these exosomes contain microRNAs (miRNAs) that could alter chemo-susceptibility, which is partly attributed to the successful intercellular transfer of multidrug resistance (MDR)-specific miRNAs. We also confirmed that β-elemene could influence MDR-related miRNA expression and regulate the expression of the target genes PTEN and Pgp, which may lead to the reversal of the chemoresistant breast cancer (BCA) cells. We are the first to report these findings, and we propose the following logical hypothesis: β-elemene can mediate MDR-related miRNA expression in cells, thereby affecting the exosome contents, reducing chemoresistance transmission via exosomes, and reversing the drug resistance of breast cancer cells. Methods: MTT-cytotoxic, miRNA microarray, real-time quantitative PCR, Dual Luciferase Activity Assay, and Western blot analysis were performed to investigate the impact of β-elemene on the expression of chemoresistance specific miRNA and PTEN as well as Pgp in chemoresistant BCA exosomes. Results: Drug resistance can be reversed by β-elemene related to exosomes. There were 104 differentially expressed miRNAs in the exosomes of two chemoresistant BCA cells: adriacin (Adr) - resistant MCF-7 cells (MCF-7/Adr) and docetaxel (Doc) - resistant MCF-7 cells (MCF-7/Doc) that underwent treatment. Of these, 31 miRNAs were correlated with the constant changes in the MDR. The expression of miR-34a and miR-452 can lead to changes in the characteristics of two chemoresistant BCA exosomes: MCF-7/Adr exosomes (A/exo) and MCF-7/Doc exosomes (D/exo). The PTEN expression affected by β-elemene was significantly increased, and the Pgp expression affected by β-elemene was significantly decreased in both cells and exosomes. β-elemene induced a significant increase in the apoptosis rate in both MCF-7/Doc and MCF-7/Adr cells. Conclusions: Drug resistance can be reversed by β-elemene, which can alter the expression of some MDR-related miRNAs, including PTEN and Pgp in MCF-7/Adr and MCF-7/Doc in cells. It can therefore affect the exosome contents and induce the reduction of resistance transmission via exosomes.

Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer

“…Thus, the exosomes play a role in the establishment of the metastatic niche by communication between cancer cells and normal cells [17]. Increasing evidence indicates that extracellular miRNAs can have a significant role in tumor progression [18, 19]. In the present study, the oncomiR miR-1246 was significantly enriched in exosomes and was responsible for the promotion of the metastatic potential of MDA-MB-231 cells.…”

Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes?

“…It is reported β-Elemene could reverse the chemoresistance by downregulate multidrug resistance microRNA in exosomes derived from chemoresistant breast cancer cell lines [103]. Low expression of miR-718 in exosomes in HCC has been reported as a risk factor for tumor recurrence after liver transplantation [104].…”

The Dual Regulatory Role of MiR-181a in Breast Cancer

“…Since the discovery of miRNAs within EVs (ex-miRNAs) in 2008, ex-miRNAs have been the subject of much research in the field of molecular and cellular biology. The main reason for this interest is that circulating ex-miRNAs mediate both short- and long-range communication between various cells, and could impact diverse physiological and pathological processes [55, 58-61]. Ex-miRNAs are relatively stable and are present in certain cancers, making them strong candidates as biological markers.…”