Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells.
Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells.
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DOI：
10.1242/jcs.178293
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Mittler R
中科院分区：
文献类型：
--
作者：
Holt SH;Darash-Yahana M;Sohn YS;Song L;Karmi O;Tamir S;Michaeli D;Luo Y;Paddock ML;Jennings PA;Onuchic JN;Azad RK;Pikarsky E;Cabantchik IZ;Nechushtai R;Mittler R
维持铁（Fe）离子和活性氧类稳态对于细胞功能、线粒体完整性和细胞死亡途径的调节是必不可少的，并且被认为是衰老和各种疾病（例如糖尿病、神经退行性疾病和癌症）的分子基础的关键过程。营养剥夺自噬因子1（Nutrient-deprivation autophagy factor 1，NAF-1，CISD 2）是一类新发现的铁硫蛋白，主要分布于线粒体外膜和内质网。它涉及调节Fe离子的稳态，以及通过与BCL-2相互作用激活自噬。在这里，我们表明，小发夹（sh）RNA介导的抑制NAF-1的结果在上皮性乳腺癌细胞和异种移植肿瘤的凋亡激活。NAF-1的抑制导致细胞对Fe离子的摄取增加，这是一种代谢转变，使细胞对糖酵解抑制剂更敏感，并激活了与HIF 1 α相关的细胞应激途径。我们的研究表明，NAF-1是一个主要的球员在乳腺癌细胞的代谢调节，通过其对细胞铁离子分布，线粒体代谢和诱导凋亡的影响。总结：NAF-1通过影响细胞内铁离子分布、线粒体代谢和诱导细胞凋亡，在乳腺癌细胞的代谢调节中发挥重要作用。
Maintaining iron (Fe) ion and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases, such as diabetes, neurodegenerative diseases and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1; also known as CISD2) belongs to a newly discovered class of Fe-sulfur proteins that are localized to the outer mitochondrial membrane and the endoplasmic reticulum. It has been implicated in regulating homeostasis of Fe ions, as well as the activation of autophagy through interaction with BCL-2. Here we show that small hairpin (sh)RNA-mediated suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased uptake of Fe ions into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways that are associated with HIF1α. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular Fe ion distribution, mitochondrial metabolism and the induction of apoptosis. Summary: NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular Fe ion distribution, mitochondrial metabolism and the induction of apoptosis.