Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Cisplatin-resistant MDA-MB-231 Cell-derived Exosomes Increase the Resistance of Recipient Cells in an Exosomal miR-423-5p-dependent Manner

Author(s): Bing Wang, Yuzhu Zhang, Meina Ye, Jingjing Wu, Lina Ma and Hongfeng Chen*

Volume 20, Issue 10, 2019

Page: [804 - 814] Pages: 11

DOI: 10.2174/1389200220666190819151946

Price: $65

Abstract

Background: Chemoresistance blunts the therapeutic effect of cisplatin (DDP) on Triple-Negative Breast Cancer (TNBC). Researchers have not determined to date whether exosomes confer DDP resistance to other breast cancer cells or whether exosomal transfer of miRNAs derived from DDP-resistant TNBC cells confer DDP resistance.

Objective: The aim of this study was to investigate the role of exosomes in chemoresistance in breast cancer.

Methods: MDA-MB-231 cells resistant to DDP (231/DDP) were established. Exosomes were isolated from 231/DDP cells (DDP/EXO) and characterized by measuring the levels of protein markers, nanoparticle tracking analysis and transmission electron microscopy. MDA-MB-231, MCF-7 and SKBR-3 cell lines were treated with the isolated DDP/EXOs and cell proliferation and cytotoxicity to DDP were evaluated using MTT assays and apoptosis analyses. Western blotting was used to examine P-glycoprotein (P-gp) expression. Additionally, a microarray was used to analyse microRNA (miRNA) expression profiles in MDA-MB-231 and 231/DDP exosomes. The effects on miRNAs were determined using RT-PCR. Exosomal miR-423-5p was extracted, and differential expression was verified. The MTT cell viability assay, flow cytometry, and Transwell and immunofluorescence assays were performed to determine if differential expression of miR-423-5p sensitized cells to DDP in vitro.

Results: Under a transmission electron microscope, the isolated exosomes exhibited a round or oval shape with a diameter ranging between 40 and 100 nm. DDP/EXOs labelled with PKH67 were taken up by MDA-MB-231 cells. After an incubation with DDP/EXOs, the cell lines exhibited a higher IC50 value for cisplatin, P-gp expression, migration and invasion capabilities and a lower apoptosis rate. Furthermore, 60 miRNAs from exosomes derived from 231/DDP cells were significantly up-regulated compared to exosomes from MDA-MB-231 cells. Notably, compared to the corresponding sensitive exosomes, miR-370-3p, miR-423-5p and miR-373 were the most differentially expressed miRNAs in DDP-resistant exosomes. We chose miR-423-5p, and up-regulation and down-regulation of exosomal miR-423-5p expression significantly affected DDP resistance.

Conclusions: Exosomes from DDP-resistant TNBC cells (231/DDP) altered the sensitivity of other breast cancer cells to DDP in an exosomal miR-423-5p dependent manner. Our research helps to elucidate the mechanism of DDP resistance in breast cancer.

Keywords: DDP resistance, exosomes, miR-423-5p, cisplatin, breast cancer, in vitro.

« Previous Next »
Graphical Abstract

[1]
Sharma, P. Biology and management of patients with triple-negative breast cancer. Oncologist, 2016, 21(9), 1050-1062.
[http://dx.doi.org/10.1634/theoncologist.2016-0067] [PMID: 27401886]
[2]
Székely, B.; Silber, A.L.; Pusztai, L. New therapeutic strategies for triple-negative breast cancer. Oncology (Williston Park), 2017, 31(2), 130-137.
[PMID: 28205193]
[3]
Liu, J.; Chen, X.; Ward, T.; Pegram, M.; Shen, K. Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer. Tumour Biol., 2017, 37(7), 9825-9835.
[http://dx.doi.org/10.1007/s13277-015-4650-1] [PMID: 26810188]
[4]
Zhang, Y.; Bao, C.; Mu, Q.; Chen, J.; Wang, J.; Mi, Y.; Sayari, A.J.; Chen, Y.; Guo, M. Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells. Neoplasma, 2016, 63(3), 362-370.
[http://dx.doi.org/10.4149/304_150806N433] [PMID: 26925782]
[5]
Cai, Y.; Tan, X.; Liu, J.; Shen, Y.; Wu, D.; Ren, M.; Huang, P.; Yu, D. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin. J. Cancer Res., 2014, 26(5), 564-572.
[PMID: 25400422]
[6]
Batrakova, E.V.; Kim, M.S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J. Control. Release, 2015, 219, 396-405.
[http://dx.doi.org/10.1016/j.jconrel.2015.07.030] [PMID: 26241750]
[7]
Yu, S.; Cao, H.; Shen, B.; Feng, J. Tumor-derived exosomes in cancer progression and treatment failure. Oncotarget, 2015, 6(35), 37151-37168.
[http://dx.doi.org/10.18632/oncotarget.6022] [PMID: 26452221]
[8]
He, C.; Zheng, S.; Luo, Y.; Wang, B. Exosome theranostics: Biology and translational medicine. Theranostics, 2018, 8(1), 237-255.
[http://dx.doi.org/10.7150/thno.21945] [PMID: 29290805]
[9]
Zomer, A.; Maynard, C.; Verweij, F.J.; Kamermans, A.; Schäfer, R.; Beerling, E.; Schiffelers, R.M.; de Wit, E.; Berenguer, J.; Ellenbroek, S.I.J.; Wurdinger, T.; Pegtel, D.M.; van Rheenen, J. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell, 2015, 161(5), 1046-1057.
[http://dx.doi.org/10.1016/j.cell.2015.04.042] [PMID: 26000481]
[10]
Di Vizio, D.; Kim, J.; Hager, M.H.; Morello, M.; Yang, W.; Lafargue, C.J.; True, L.D.; Rubin, M.A.; Adam, R.M.; Beroukhim, R.; Demichelis, F.; Freeman, M.R. Oncosome formation in prostate cancer: Association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res., 2009, 69(13), 5601-5609.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3860] [PMID: 19549916]
[11]
Ma, L.; Teruya-Feldstein, J.; Weinberg, R.A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 2007, 449(7163), 682-688.
[http://dx.doi.org/10.1038/nature06174] [PMID: 17898713]
[12]
Penna, E.; Orso, F.; Taverna, D. miR-214 as a key hub that controls cancer networks: Small player, multiple functions. J. Invest. Dermatol., 2015, 135(4), 960-969.
[http://dx.doi.org/10.1038/jid.2014.479] [PMID: 25501033]
[13]
Xie, J.; Yu, F.; Li, D.; Zhu, X.; Zhang, X.; Lv, Z. MicroRNA-218 regulates cisplatin (DPP) chemosensitivity in non-small cell lung cancer by targeting RUNX2. Tumour Biol., 2016, 37(1), 1197-1204.
[http://dx.doi.org/10.1007/s13277-015-3831-2] [PMID: 26282001]
[14]
Morel, L.; Regan, M.; Higashimori, H.; Ng, S.K.; Esau, C.; Vidensky, S.; Rothstein, J.; Yang, Y. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem., 2013, 288(10), 7105-7116.
[http://dx.doi.org/10.1074/jbc.M112.410944] [PMID: 23364798]
[15]
Chiba, M.; Kimura, M.; Asari, S. Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol. Rep., 2012, 28(5), 1551-1558.
[http://dx.doi.org/10.3892/or.2012.1967] [PMID: 22895844]
[16]
Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J.J.; Lötvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol., 2007, 9(6), 654-659.
[http://dx.doi.org/10.1038/ncb1596] [PMID: 17486113]
[17]
Qin, X.; Yu, S.; Xu, X.; Shen, B.; Feng, J. Comparative analysis of microRNA expression profiles between A549, A549/DDP and their respective exosomes. Oncotarget, 2017, 8(26), 42125-42135.
[http://dx.doi.org/10.18632/oncotarget.15009] [PMID: 28178672]
[18]
Au Yeung, C.L.; Co, N.N.; Tsuruga, T.; Yeung, T.L.; Kwan, S.Y.; Leung, C.S.; Li, Y.; Lu, E.S.; Kwan, K.; Wong, K.K.; Schmandt, R.; Lu, K.H.; Mok, S.C. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat. Commun., 2016, 7, 11150.
[http://dx.doi.org/10.1038/ncomms11150] [PMID: 27021436]
[19]
Yan, Y.; Fu, G.; Ye, Y.; Ming, L. Exosomes participate in the carcinogenesis and the malignant behavior of gastric cancer. Scand. J. Gastroenterol., 2017, 52(5), 499-504.
[http://dx.doi.org/10.1080/00365521.2016.1278458] [PMID: 28128667]
[20]
Zhang, J.P.; Zeng, C.; Xu, L.; Gong, J.; Fang, J.H.; Zhuang, S.M. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting met/Snail signaling. Oncogene, 2014, 33(31), 4069-4076.
[http://dx.doi.org/10.1038/onc.2013.369] [PMID: 24013226]
[21]
Sheng, J.Y.; Shi, B.L.; Chen, H.F. Establishment and appraisal of DDP resistant variant of triple negative breast cancer cell line MDA-MB-231. Zhongliu Fangzhi Yanjiu, 2016, 43, 175-180.
[22]
Lv, M.M.; Zhu, X.Y.; Chen, W.X.; Zhong, S.L.; Hu, Q.; Ma, T.F.; Zhang, J.; Chen, L.; Tang, J.H.; Zhao, J.H. Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumour Biol., 2014, 35(11), 10773-10779.
[http://dx.doi.org/10.1007/s13277-014-2377-z] [PMID: 25077924]
[23]
Xiao, X.; Yu, S.; Li, S.; Wu, J.; Ma, R.; Cao, H.; Zhu, Y.; Feng, J. Exosomes: Decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One, 2014, 9(2)e89534
[http://dx.doi.org/10.1371/journal.pone.0089534] [PMID: 24586853]
[24]
Tanaka, Y.; Kamohara, H.; Kinoshita, K.; Kurashige, J.; Ishimoto, T.; Iwatsuki, M.; Watanabe, M.; Baba, H. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer, 2013, 119(6), 1159-1167.
[http://dx.doi.org/10.1002/cncr.27895] [PMID: 23224754]
[25]
Xiao, D.; Ohlendorf, J.; Chen, Y.; Taylor, D.D.; Rai, S.N.; Waigel, S.; Zacharias, W.; Hao, H.; McMasters, K.M. Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PLoS One, 2012, 7(10)e46874
[http://dx.doi.org/10.1371/journal.pone.0046874] [PMID: 23056502]
[26]
Li, S.; Zeng, A.; Hu, Q.; Yan, W.; Liu, Y.; You, Y. miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas. Neuro-oncol., 2017, 19(1), 55-65.
[http://dx.doi.org/10.1093/neuonc/now129] [PMID: 27471108]
[27]
Jia, W.; Yu, T.; An, Q.; Cao, X.; Pan, H. MicroRNA-423-5p inhibits colon cancer growth by promoting caspase-dependent apoptosis. Exp. Ther. Med., 2018, 16(2), 1225-1231.
[http://dx.doi.org/10.3892/etm.2018.6288] [PMID: 30116373]

Rights & Permissions Print Cite
Article Metrics
99
29
© 2024 Bentham Science Publishers | Privacy Policy