Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

Abstract

Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100–5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100–5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100–5p. Exosomes confer recipient cells’ resistance to DDP in an exosomal miR-100–5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells’ sensitivity to DDP in exosomal miR-100–5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.

Exosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway

“…25,29 In NSCLC, exosome-transmitted miR-222-3p also functioned as a principle regulator of gemcitabine resistance and exosome-transmitted miR-100-5p regulates DDP resistance. 15,26 In addition to miRNA, Le Qu et al 14 Besides, epithelial-mesenchymal transition (EMT) has been associated with acquired resistance to EGFR-TKIs, with a decrease in epithelial markers such as E-cadherin and an increase in mesenchymal markers such as vimentin. 30 Richard et al 31 We first discussed the roles of exosomes shed by EGFR-TKI-resistant NSCLC cells harbouring T790M mutation in drug resistance transmission.…”

MiR-100 inhibits invasion and migration of nasopharyngeal carcinoma cells by regulating ZBTB7A gene

“…While miRNA-100 was blocked, its invasion and migration abilities increased significantly, displaying its influence on metastasis of nasopharyngeal carcinoma [4]. Expressions of miR-100 and ZBTB7A mRNA in nasopharyngeal carcinoma cells were detected by fluorescence quantitative PCR.…”

Potential role of exosomes in cancer therapy

“…Inhibition of AKT1 can result in activation of autophagy consequently leading to the resistance of non‐small‐cell lung carcinoma cells to DDP treatment . Downregulated exosomal miR‐100–5p was also proved to be involved in DDP resistance through the mammalian target of rapamycin signaling pathway in A549 cells . In addition, the overexpression of exosomal miR‐146a‐5p could reverse the resistance of A549/DDP by targeting Atg12 to inhibit autophagy .…”

“…22 Downregulated exosomal miR-100-5p was also proved to be involved in DDP resistance through the mammalian target of rapamycin signaling pathway in A549 cells. 23 In addition, the overexpression of exosomal miR-146a-5p could reverse the resistance of A549/DDP by targeting Atg12 to inhibit autophagy. 24 Exosomal miR-222-3p functioned as a principal regulator of gemcitabine resistance and malignant characteristics by targeting SOCS3, which might be a potential prognostic biomarker for predicting gemcitabine sensitivity in NSCLC patients.…”