H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties
H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties
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DOI：
10.1182/blood.v94.10.3593.422k26_3593_3603
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发表时间：
1999-11-15
期刊：
影响因子：
20.3
通讯作者：
Cabantchik, ZI
中科院分区：
文献类型：
--
作者：
Epsztejn, S;Glickstein, H;Cabantchik, ZI
动物细胞的不稳定铁库（LIP）参与细胞铁的调节，是氧化应激反应的重要组成部分。LIP下调的一个主要机制是铁蛋白（FT）的诱导表达，特别是显示铁氧化酶活性的重亚基（H-FT）。在稳定转染H-FT亚基的小鼠红白血病（MEL）细胞中，研究了H-FI对LIP和其他生理参数的影响。表达不同水平H-FT的克隆显示出相似的总细胞铁浓度（0.3 +/-0.1 mmol/L）和还原型/总谷胱甘肽浓度。然而，随着H-FT的增加，细胞表达较低水平的LIP和活性氧（ROS），并随后在铁蟾蜍和氧化挑战后细胞死亡。这些结果为H-FT作为不稳定细胞铁的调节剂和作为氧化细胞反应的可能衰减剂的所谓作用提供了直接的实验支持。H-FT过表达对细胞增殖能力无明显影响。然而，随着铁和氧化还原调节能力的获得，H-FT转染细胞最终获得了多药耐药（MDR）特性。这些特性被鉴定为MDR1 mRNA表达增加（通过逆转录聚合酶链反应[RT-PCR]），P-糖蛋白（Western免疫印迹法），药物转运活性（维拉帕米敏感的药物外排）和与增加的MDR 1或PgP相关的药物细胞毒性。尽管增强的MDR表达本身在LIP释放或ROS产生方面没有引起显著变化，它可能是H-FT转染子存活所必需的，可能是通过加速细胞产生的代谢物的输出。(C)1999年，美国血液学会。
The labile iron pool (LIP) of animal cells has been implicated in cell iron regulation and as a key component of the oxidative-stress response. A major mechanism commonly implied in the downregulation of LIP has been the induced expression of ferritin (FT), particularly the heavy subunits (H-FT) that display ferroxidase activity. The effects of H-FI on LIP and other physiological parameters were studied in murine erythroleukemia (MEL) cells stably transfected with H-FT subunits. Clones expressing different levels of H-FT displayed similar concentrations of total cell iron (0.3 +/- 0.1 mmol/L) and of reduced/total glutathione. However, with increasing H-FT revels the cells expressed lower levels of LIP and reactive oxygen species (ROS) and ensuing cell death after iron toads and oxidative challenges. These results provide direct experimental support for the alleged roles of H-FT as a regulator of labile cell iron and as a possible attenuator of the oxidative cell response. H-FT overexpression was of no apparent consequence to the cellular proliferative capacity. However, concomitant with the acquisition of iron and redox regulatory capacities, the H-FT-transfectant cells commensurately acquired multidrug resistance (MDR) properties. These properties were identified as increased expression of MDR1 mRNA (by reverse transcription polymerase chain reaction [RT-PCR]), P-glycoprotein (Western immunoblotting), drug transport activity (verapamil-sensitive drug efflux), and drug cytotoxicity associated with increased MDR1 or PgP Although enhanced MDR expression per se evoked no significant changes in either LIP revels or ROS production, it might be essential for the survival of H-FT transfectants, possibly by expediting the export of cell-generated metabolites. (C) 1999 by The American Society of Hematology.