Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters
Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters
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DOI：
10.1073/pnas.1612736113
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发表时间：
2016-09-27
影响因子：
11.1
通讯作者：
Nechushtai, Rachel
中科院分区：
文献类型：
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作者：
Darash-Yahana, Merav;Pozniak, Yair;Nechushtai, Rachel
铁硫（Fe-S）蛋白被认为在癌细胞介导氧化还原反应、DNA复制和端粒维持中发挥重要作用。营养剥夺自噬因子-1 （naf1）是一种与多种癌症进展相关的2Fe(2)S蛋白。它在Fe-S蛋白中是独一无二的，因为它的3Cys-1His簇配位结构使它相对稳定，并且可以将其簇转移到载脂蛋白受体蛋白上。在这里，我们报道了naf1在异种移植乳腺癌肿瘤中的过度表达导致肿瘤大小和侵袭性的显着增加，并且naf1的过度表达增强了癌细胞对氧化应激的耐受性。值得注意的是，在异种移植乳腺癌肿瘤中，过度表达具有稳定naf1簇的单点突变的naf1突变体naf1 （H114C）会导致肿瘤大小急剧减小，同时伴随着线粒体铁和活性氧积累的增强，以及细胞对氧化应激的耐受性降低。此外，用稳定3cs - 1his nf -1簇的吡格列酮治疗乳腺癌细胞，对线粒体铁和活性氧积累产生类似的影响。综上所述，我们的发现指出了独特的3cs - 1his nf -1簇在通过细胞抵抗氧化应激促进肿瘤快速生长中的关键作用。因此，由过表达的naf1蛋白介导的簇转移反应对于诱导癌细胞的氧化应激耐受性至关重要，从而导致肿瘤快速生长，稳定naf1簇的药物可以作为naf1高表达癌症治疗策略的一部分。
Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe(2)S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, over-expression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.