Exosomes are small extracellular membrane vesicles of endocytic origin released by many cells that could be found in most body fluids. The main functions of exosomes are cellular communication and cellular waste clean-up. This study was conducted to determine the involvement of exosomes in the regulation of sensitivity of the lung cancer cell line A549 to cisplatin (DDP). When DDP was added to A549 cells, exosomes secretion was strengthened. Addition of the secreted exosomes to other A549 cells increased the resistance of these A549 cells to DDP. Upon exposure of A549 to DDP, the expression levels of several miRNAs and mRNAs reportedly associated with DDP sensitivity changed significantly in exosomes; these changes may mediate the resistance of A549 cells to DDP. Exosomes released by A549 cells during DDP exposure decreased the sensitivity of other A549 cells to DDP, which may be mediated by miRNAs and mRNAs exchange by exosomes via cell-to-cell communication. Although the detailed mechanism of resistance remains unclear, we believed that inhibition of exosomes formation and release might present a novel strategy for lung cancer treatment in the future.
Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM (2008) The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 48: 495–535. doi: 10.1146/annurev.pharmtox.48.080907.180426
Eastman A (1987) The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther 34: 155–166. doi: 10.1016/0163-7258(87)90009-x
Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319: 1352–1355. doi: 10.1126/science.1140735
Zhang G, Sun L, Lu X, Chen Z, Duerksen-Hughes PJ, et al. (2012) Cisplatin treatment leads to changes in nuclear protein and microRNA expression. Mutat Res 746: 66–77. doi: 10.1016/j.mrgentox.2012.03.004
Shellard SA, Fichtinger-schepman AM, Lazo JS, Hill BT (1993) Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. Anticancer Drugs 4: 491–500. doi: 10.1097/00001813-199308000-00011
Galluzzi L, Moreslli E, Vitale I, Kepp O, Senovilla L, et al. (2010) MiR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 70: 1793–1803. doi: 10.1158/0008-5472.can-09-3112
Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, et al. (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7: 297–303.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, et al. (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9: 654–659. doi: 10.1038/ncb1596
Whiteside TL (2013) Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 41: 245–251. doi: 10.1042/bst20120265
Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, et al. (2013) Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 335: 201–204. doi: 10.1016/j.canlet.2013.02.019
SKOG J, Wuringer T, Van Rijn S, Meijer DH, Gainche L, et al. (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10: 1470–1476. doi: 10.1038/ncb1800
Corcoran C, Rani S, O’brien K, O’Neilll A, Prencipe M, et al. (2012) Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 7: e50999. doi: 10.1371/journal.pone.0050999
Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, et al. (2010) Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 5: e13247. doi: 10.1371/journal.pone.0013247
Xin H, Li Y, Buller B, Katakowski M, Zhang Y, et al. (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30: 1556–1564. doi: 10.1002/stem.1129
Gao W, Lu X, Liu L, Xu J, Feng D, et al. (2012) MiRNA-21: a biomarker predictive for platinum-based adjuvant chemotherapy response in patients with non-small cell lung cancer. Cancer Biol Ther 13: 330–340. doi: 10.4161/cbt.19073
Xiang Q, Tang H, Yu J, Yin J, Yang X, et al. (2013) MicroRNA-98 sensitizes cisplatin-resistant human lung adenocarcinoma cells by up-regulation of HMGA2. Pharmazie 68: 274–281.
Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, et al. (2010) MiR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 70: 1793–1803. doi: 10.1158/0008-5472.can-09-3112
Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, et al. (2010) Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res 8: 1207–1216. doi: 10.1158/1541-7786.mcr-10-0052
Gao Y, Zhu J, Zhang X, Wu Q, Jiang S, et al. (2013) BRCA1 mRNA Expression as a Predictive and Prognostic Marker in Advanced Esophageal Squamous cell Carcinoma Treated with Cisplatin- or Docetaxel-Based Chemotherapy/Chemoradiotherapy. PLoS One 8: e52589. doi: 10.1371/journal.pone.0052589
Wu Y, Crawford M, Yu B, Mao Y, Nana-Sinkam SP, et al. (2011) MicroRNA delivery by cationic lipoplexes for lung cancer therapy. Mol Pharm 8: 1381–1389. doi: 10.1021/mp2002076
Eldh M, Ekstrom K, Valadi H, Sjostrand M, Olsson B, et al. (2010) Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One 5: e15353. doi: 10.1371/journal.pone.0015353
