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低甲基化剂诱导耐药后 MOLM-13 细胞系中凋亡途径的变化。

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents.

机构信息

Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava, Slovakia.

Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovakia.

出版信息

Int J Mol Sci. 2021 Feb 19;22(4):2076. doi: 10.3390/ijms22042076.

DOI:10.3390/ijms22042076
PMID:33669837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7923013/
Abstract

We established the following two variants of the MOLM-13 human acute myeloid leukemia (AML) cell line: (i) MOLM-13/DAC cells are resistant to 5-aza-2'-deoxycytidine (DAC), and (ii) MOLM-13/AZA are resistant to 5-azacytidine (AZA). Both cell variants were obtained through a six-month selection/adaptation procedure with a stepwise increase in the concentration of either DAC or AZA. MOLM-13/DAC cells are resistant to DAC, and MOLM-13/AZA cells are resistant to AZA (approximately 50-fold and 20-fold, respectively), but cross-resistance of MOLM-13/DAC to AZA and of MOLM-13/AZA to DAC was not detected. By measuring the cell retention of fluorescein-linked annexin V and propidium iodide, we showed an apoptotic mode of death for MOLM-13 cells after treatment with either DAC or AZA, for MOLM-13/DAC cells after treatment with AZA, and for MOLM-13/AZA cells after treatment with DAC. When cells progressed to apoptosis, via JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) assay, we detected a reduction in the mitochondrial membrane potential. Furthermore, we characterized promoter methylation levels for some genes encoding proteins regulating apoptosis and the relation of this methylation to the expression of the respective genes. In addition, we focused on determining the expression levels and activity of intrinsic and extrinsic apoptosis pathway proteins.

摘要

我们建立了以下两种人急性髓系白血病（AML）MOLM-13 细胞系的变体：（i）MOLM-13/DAC 细胞对 5-氮杂-2'-脱氧胞苷（DAC）具有抗性，（ii）MOLM-13/AZA 细胞对 5-氮杂胞苷（AZA）具有抗性。这两种细胞变体均通过六个月的选择/适应程序获得，该程序逐步增加 DAC 或 AZA 的浓度。MOLM-13/DAC 细胞对 DAC 具有抗性，MOLM-13/AZA 细胞对 AZA 具有抗性（分别约为 50 倍和 20 倍），但未检测到 MOLM-13/DAC 对 AZA 的交叉抗性和 MOLM-13/AZA 对 DAC 的交叉抗性。通过测量荧光素缀合的膜联蛋白 V 和碘化丙啶的细胞保留率，我们表明 MOLM-13 细胞在用 DAC 或 AZA 处理后，MOLM-13/DAC 细胞在用 AZA 处理后，以及 MOLM-13/AZA 细胞在用 DAC 处理后，均以凋亡方式死亡。当细胞通过 JC-1（5,5',6,6'-四氯-1,1',3,3'-四乙基-碘化咪唑羰花青）测定法进展为凋亡时，我们检测到线粒体膜电位降低。此外，我们对一些编码调节细胞凋亡的蛋白质的基因的启动子甲基化水平及其与相应基因表达的关系进行了表征。此外，我们专注于确定内在和外在凋亡途径蛋白的表达水平和活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f78a/7923013/65911784d149/ijms-22-02076-g010.jpg
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