In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin
In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin
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DOI：
10.1182/blood-2006-04-018341
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发表时间：
2006-10-01
期刊：
影响因子：
20.3
通讯作者：
Ponka, Prem
中科院分区：
文献类型：
--
作者：
Nie, Guangjun;Chen, Guohua;Ponka, Prem
线粒体铁蛋白（MtFt）是一种线粒体铁储存蛋白，其功能和调控在很大程度上是未知的。我们以前的研究结果表明，MtFt过表达显着影响哺乳动物细胞内铁稳态。使用肿瘤异种移植物，我们研究了MtFt过表达对肿瘤铁代谢和生长的影响。MtFt的表达显著降低了裸鼠移植瘤的生长。通过透射电子显微镜直接观察到MtFt表达肿瘤中的线粒体铁沉积。一个胞质铁饥饿表型在MtFt表达肿瘤的铁调节蛋白的RNA结合活性增加，并伴随着转铁蛋白受体水平的增加和胞质铁蛋白的减少。MtFt过表达还导致总细胞血红素含量和血红素加氧酶-1水平降低。此外，肿瘤中MtFt升高还与总顺乌头酸酶活性降低和共济失调蛋白水平降低相关。总之，我们的研究表明，高MtFt水平可以通过将铁分流到线粒体中来显著影响肿瘤铁稳态;铁缺乏导致部分缺乏血红素和铁硫簇合成。很可能细胞质中铁的缺乏是异种移植肿瘤生长显著抑制的原因。
Mitochondrial ferritin (MtFt) is a mitochondrial iron-storage protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular iron homeostasis in mammalian cells. Using tumor xenografts, we examined the effects of MtFt overexpression on tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted tumor growth in nude mice. Mitochondrial iron deposition in MtFt-expressing tumors was directly observed by transmission electron microscopy. A cytosolic iron starvation phenotype in MtFt-expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins, and concomitantly both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to decreases in total cellular heme content and heme oxygenase-1 levels. In addition, elevated MtFt in tumors was also associated with a decrease in total aconitase activity and lower frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partially deficient heme and iron-sulfur cluster synthesis. It is likely that deprivation of iron in the cytosol is the cause for the significant inhibition of xenograft tumor growth.