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编者按：以下数据来自以色列和美国的实验室研究结果，无法完全代表中国患者实际情况和临床医生具体意见。以下原文为在线预先发表版，并非最终正式发表版。以下文字由谷歌翻译提供支持，欢迎留言提出修改建议，谢谢！ 相关阅读 既往研究已经证实糖尿病常用药物二甲双胍能够抗乳腺癌。 2016年9月12日，美国《国家科学院院刊》在线发表以色列希伯来大学、特拉维夫大学、美国莱斯大学、北德克萨斯大学、圣迭戈加利福尼亚大学的研究报告，发现通过另一种糖尿病常用药物吡格列酮可对抗乳腺癌细胞增殖相关蛋白质过度表达。 该研究发现一种抑制乳腺癌增殖相关特殊蛋白质过度表达的新方法，降低营养素剥夺自噬因子-1（NAF-1）水平及其运输的铁硫（Fe-S）簇活性可能有助于抑制乳腺癌生长。 NAF-1是一个传感器，就像一个跷跷板，告诉细胞正在失去平衡，并且努力地将其纠正。但是，一旦有任何失衡，细胞就会死亡。NAF-1属于NEET蛋白质家族，能够运输铁硫簇，而铁硫簇能够通过控制细胞还原氧化作用和代谢活性，有助于调节细胞代谢过程。自然状态下，铁硫簇能够吸附到线粒体外表面，线粒体是为细胞提供化学能的“发电厂”。NAF-1过度表达可增强乳腺癌细胞对氧化应激的耐受能力，从而促进肿瘤生长并更具有侵袭性。过度表达NAF-1的癌细胞对于特殊类型药物比较敏感，因此可以设计新型药物阻断铁硫簇的功能，进而抑制肿瘤生长。该研究利用一种全面方法阐明NAF-1在乳腺癌中的机制，理解这一机制，将有助于改善计算机模拟，辅助新药物的快速设计和检测。 吡格列酮可能有效控制NAF-1水平，NAF-1单突变几乎完全阻断癌细胞增殖能力支持该假设，即降低NAF-1水平能够帮助阻断肿瘤。通过对这种药物进行调整，特异性地针对肿瘤，或许能够提供一种强大武器帮助抵抗乳腺癌或其他癌症。除了乳腺癌，NAF-1过度表达还与前列腺癌、胃癌、宫颈癌、肝癌、喉癌相关。 吡格列酮可稳定NAF-1中的铁硫簇，降低癌细胞的抗氧化性和对氧化应激的耐受性，从而抑制肿瘤。已知5～6种癌细胞需要NAF-1才能生存增殖，如果没有NAF-1，这些癌细胞就不能生存。该研究还发现，一种携带一个单点突变的NAF-1蛋白的表达，可对癌细胞产生相似的毒性作用而抑制癌细胞增殖。 肿瘤依赖于铁硫簇的易变性或瞬态性能，拥有NAF-1越多，其所运输的铁硫簇就越多，肿瘤生长就越快。既往研究发现吡格列酮可稳定铁硫簇，而在突变体中很难发现任何肿瘤，也观察不到任何肿瘤血管发生。 该研究通过计算机模拟显示结合位点在哪里，尝试一种药物就像突变一样也稳定这个铁硫簇，以及为什么药物能稳定铁硫簇。通过计算机建模预测蛋白质折叠途径，能准确显示如何修改这种药物，可以在制造真正的药物之前，通过计算机设计药物，这是实现该可能性的一种更便宜的方式。未来可以设计出仅结合NAF-1（而不是其他蛋白质）的选择性药物，在有效降低药物副作用同时，还能有效抑制肿瘤的发生和发展。 Powered by Google Translate Proc Natl Acad Sci U S A. 2016 Sep 12. [Epub ahead of print] Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters. Merav Darash-Yahana, Yair Pozniak, Mingyang Lu, Yang-Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A. Jennings, Eli Pikarsky, Tamar Geiger, José N. Onuchic, Ron Mittler, Rachel Nechushtai. Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel; Tel Aviv University, Tel Aviv 6997801, Israel; Rice University, Houston, TX 77005; University of North Texas, Denton TX 76203; University of California at San Diego, La Jolla, CA 92093; Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. SIGNIFICANCE: Elevated expression of the iron-sulfur (Fe-S) protein nutrient-deprivation autophagy factor-1 (NAF-1) is associated with the progression of multiple cancer types. Here we demonstrate that the lability of the Fe-S cluster of NAF-1 plays a key role in promoting breast cancer cell proliferation, tumor growth, and resistance of cancer cells to oxidative stress. Our study establishes an important role for the unique 3Cys-1His Fe-S cluster coordination structure of NAF-1 in promoting the development of breast cancer tumors and suggests the potential use of drugs that suppress NAF-1 accumulation or stabilize its cluster in the treatment of cancers that display high expression levels of NAF-1. ABSTRACT: 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-2S 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, overexpression 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. DOI: 10.1073/pnas.1612736113 |
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