Tumor necrosis factor-α-induced reactive oxygen species formation is mediated by JNK1-dependent ferritin degradation and elevation of labile iron pool

被引:85
作者
Antosiewicz, Jedrzej
Ziolkowski, Wieslaw
Kaczor, Jan Jacek
Herman-Antosiewicz, Anna
机构
[1] Med Univ Gdansk, Dept Bioenerget & Physiol Exercise, PL-80211 Gdansk, Poland
[2] Univ Gdansk, Dept Mol Biol, PL-80952 Gdansk, Poland
关键词
D O I
10.1016/j.freeradbiomed.2007.04.023
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor necrosis factor alpha induces increased reactive oxygen species (ROS) generation in different experimental models. However, the nature of this phenomenon is still unknown. We hypothesized that TNF-induced ROS formation is due to JNK-regulated ferritin degradation and an increase in labile iron pool (LIP). We used as a model human prostate cancer cells, DU 145. TNF treatment induced ROS formation, which was reduced to the control level in cells pretreated with desferrioxamine, an iron chelator. TNF induced a drop in light chain of the ferritin level, as judged by immunoblotting and an increase in LIP, evaluated by calcein fluorescence. Moreover, we observed that the INK inhibitor SP600125 abolished TNF-induced changes in LIP, which suggests that JNK kinases are involved in this process. To explore which one of the JNK kinases is responsible for these effects, DU145 cells were transiently transfected with plasmids encoding inactive mutants of JNK1 or JNK2. The cells expressing inactive JNK I mutant, but not cells expressing JNK2 mutant or possessing an empty vector, were completely resistant to TNF-induced ROS generation, ferritin degradation, and an increase in LIP. These data suggest that TNF-induced ROS formation is mediated by JNKL which regulates ferritin degradation and thus the level of highly reactive iron. (C) 2007 Elsevier Inc. All rights reserved.
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收藏
页码:265 / 270
页数:6
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