MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

被引:22
作者
Kaehler, Meike [1 ]
Ruemenapp, Johanna [1 ]
Gonnermann, Daniel [2 ]
Nagel, Inga [1 ]
Bruhn, Oliver [1 ]
Haenisch, Sierk [1 ]
Ammerpohl, Ole [3 ]
Wesch, Daniela [2 ]
Cascorbi, Ingolf [1 ]
Bruckmueller, Henrike [1 ]
机构
[1] Univ Hosp Schleswig Holstein, Inst Expt & Clin Pharmacol, Campus Kiel, Kiel, Germany
[2] Univ Hosp Schleswig Holstein, Inst Immunol, Campus Kiel, Kiel, Germany
[3] Univ Hosp Schleswig Holstein, Inst Human Genet, Campus Kiel, Kiel, Germany
关键词
drug resistance; drug transporters; ABCG2; miR-212; methylation; DRUG TRANSPORTERS ABCB1; DOWN-REGULATION; BCR-ABL; MULTIDRUG-RESISTANCE; GASTRIC-CANCER; CLINICAL PHARMACOKINETICS; CYTOSINE METHYLATION; MIR-212; EXPRESSION; TUMOR-SUPPRESSOR; ABCG2;
D O I
10.18632/oncotarget.21272
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 imatinibtreatment, 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-naive cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 mu M to 2 mu M). Further analysis in treatment-naive 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 mu M 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.
引用
收藏
页码:92018 / 92031
页数:14
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