MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells
| Autor: | Ole Ammerpohl, Henrike Bruckmueller, Daniel Gonnermann, Meike Kaehler, Oliver Bruhn, Daniela Wesch, Johanna Ruemenapp, Ingolf Cascorbi, Sierk Haenisch, Inga Nagel |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.drug_class ABCG2 drug transporters Pharmacology miR-212 Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation hemic and lymphatic diseases medicine Viability assay drug resistance Kinase business.industry Myeloid leukemia Transfection 030104 developmental biology Oncology Cell culture Apoptosis 030220 oncology & carcinogenesis Cancer research methylation business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.21272 |
| Popis: | BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3′-UTR. However, the functional impact on drug sensitivity remained unknown. Therefore, we performed transfection experiments using microRNA-mimics and –inhibitors and investigated their effect on imatinib-susceptibility in sensitive and resistant leukemic cell lines. Under imatinib-treatment, miR-212 inhibition led to enhanced cell viability (p = 0.01), reduced apoptosis (p = 0.01) and cytotoxicity (p = 0.03). These effects were limited to treatment-naïve cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 μM to 2 μM). Further analysis in treatment-naïve cells revealed that miR-212 inhibition resulted in ABCG2 upregulation and increased ABCG2-dependent efflux. Furthermore, we observed miR-212 promoter hypermethylation in 0.5 and 2 μM IM-resistant sublines, whereas ABCG2 methylation status was not altered. Taken together, the miR-212/ABCG2-axis influences imatinib-susceptibility contributing to development of imatinib-resistance. Our data reveal new insights into mechanisms initiating imatinib-resistance in leukemic cells. |
| Databáze: | OpenAIRE |
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