H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties

被引:176
作者
Epsztejn, S
Glickstein, H
Picard, V
Slotki, IN
Breuer, W
Beaumont, C
Cabantchik, ZI [1 ]
机构
[1] Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel
[2] Shaare Zedek Med Ctr, Nephrol Unit, Jerusalem, Israel
[3] Fac Xavier Bichat, Paris, France
关键词
D O I
10.1182/blood.V94.10.3593.422k26_3593_3603
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:3593 / 3603
页数:11
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