Abstract
The aim of this study was to investigate signaling pathways for reversal of microRNA-127-mediated multi-drug resistance (MDR) in gliomas cells. Adriamycin-resistant glioma cell lines U251/adr and U87-MG/adr were established and we found that anti-microRNA-127 markedly reduced microRNA-127 expression levels in a time-dependent manner, leading to distinct inhibition of cell proliferation and increased apoptosis and the content of intracellular Rh123. Silencing of microRNA-127 significantly increased the sensitivity of U251/ADR and U87-MG/adr cells to adriamycin, compared to cells transfected with negative control siRNA. Silencing of microRNA-127 also significantly reduced the mRNA and protein expression levels of MDR1 and MRP1, which are major ATP-binding cassette (ABC) transporter linked to multi-drug resistance in cancer cells. And Runx2, p53, bcl-2 and survivin, which are important role in cell apoptosis, also markedly changed after microRNA-127 silencing. In addition, down-regulating microRNA-127 decreased the level of phosphorylated-Akt. Our data indicate that down-regulation of micorRNA-127 can trigger apoptosis and overcome drug resistance of gliomas cells. Therefore, this resistance of adriamycin in gliomas can be cancelled by silencing expression of microRNA-127.
Keywords:
adriamycin; drug resistance reversal; gliomas; microRNA-127.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / drug effects*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Cycle Checkpoints / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Core Binding Factor Alpha 1 Subunit / genetics
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Core Binding Factor Alpha 1 Subunit / metabolism
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Dose-Response Relationship, Drug
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Down-Regulation
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques*
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Glioma / drug therapy*
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Glioma / genetics
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Glioma / metabolism
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Glioma / pathology
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA Interference*
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Survivin
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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Antibiotics, Antineoplastic
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BCL2 protein, human
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BIRC5 protein, human
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Core Binding Factor Alpha 1 Subunit
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Inhibitor of Apoptosis Proteins
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MIRN127 microRNA, human
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MicroRNAs
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Multidrug Resistance-Associated Proteins
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Proto-Oncogene Proteins c-bcl-2
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RUNX2 protein, human
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Survivin
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TP53 protein, human
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Tumor Suppressor Protein p53
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Doxorubicin
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Proto-Oncogene Proteins c-akt
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multidrug resistance-associated protein 1