Delgado-Cañedo A, Chies J A B, Nardi N B
Genetics Department, Universidade Federal do Rio Grande do Sul, Av Bento Goncalves 9500, 91540-000 Porto Alegre, RS, Brazil.
Med Hypotheses. 2005;65(5):932-6. doi: 10.1016/j.mehy.2005.02.046.
The K562 cell line has erythroid origin and is used for the study of fetal haemoglobin (HbF) production after treatment with several drugs, such as hydroxyurea, cisplatin and cytosine arabinoside (Ara C). It represents an important tool for the study of cancer differentiation therapy and treatment of thalassaemia and sickle cell disease. Although subject to intense research, the mechanisms involved in the induction of HbF are not fully established, and the regulation of several genes and signalling pathways has been proposed. Using the methodology of differential display, we investigated the changes in gene expression in K562 cells treated with doxorubicin and aclarubicin, which induce HbF expression and cell cycle arrest. Several genes were shown to present differential expression patterns, many of them related to the iron signalling pathway. Particular attention was given to Ndrg1, expressed as early as 24 h after treatment, which can be regulated by iron and is involved with blocking of the cell cycle. A review of the literature shows that, similar to doxorubicin and aclarubicin, most of the drugs used to induce HbF present some kind of effect on the iron signalling pathway, activating in the cells the machinery necessary for the incorporation of extracellular iron. Considering these results, as well as the fact that in erythroid cells the synthesis of haemoglobin is of vital importance, we propose that the production of fetal haemoglobin in erythroid cells is highly dependent on the iron signalling pathway.
K562细胞系起源于红系，用于研究多种药物（如羟基脲、顺铂和阿糖胞苷）处理后胎儿血红蛋白（HbF）的产生。它是研究癌症分化治疗以及地中海贫血和镰状细胞病治疗的重要工具。尽管受到广泛研究，但诱导HbF产生的机制尚未完全明确，已有多种基因和信号通路参与调控的相关报道。利用差异显示方法，我们研究了阿霉素和阿柔比星处理K562细胞后基因表达的变化，这两种药物可诱导HbF表达并使细胞周期停滞。结果显示，多个基因呈现差异表达模式，其中许多与铁信号通路相关。特别关注的是Ndrg1基因，它在处理后24小时即开始表达，可受铁调控，并与细胞周期阻滞有关。文献综述表明，与阿霉素和阿柔比星类似，大多数用于诱导HbF的药物对铁信号通路都有某种作用，能在细胞内激活摄取细胞外铁所需的机制。综合这些结果，以及在红系细胞中血红蛋白合成至关重要这一事实，我们提出红系细胞中胎儿血红蛋白的产生高度依赖铁信号通路。
