Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Pathology and Laboratory Medicine, Obstetrics, Gynecology and Women's Health, and Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey.
Cancer Res. 2014 Jan 15;74(2):552-62. doi: 10.1158/0008-5472.CAN-13-0474. Epub 2013 Nov 12.
Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.
癌症的病因受蛋白质合成改变的影响，但这些改变尚未完全被理解。在这项研究中，我们采用了一种新方法来研究真核翻译起始因子 eIF5A 在人宫颈癌中的作用，该因子在宫颈癌中广泛过表达。eIF5A 含有独特的氨基酸 hypusine，它是通过需要脱氧hypusine 羟化酶（DOHH）的翻译后修饰事件形成的，该酶可被药物环吡酮和地拉罗司抑制。我们发现，用这两种药物中的任何一种抑制 DOHH，或用 RNA 干扰沉默 eIF5A、DOHH 或 hypusine 途径中的另一种酶，都可以阻断宫颈癌细胞的增殖。在 HeLa 宫颈癌细胞中的蛋白质组学和 RNA 分析鉴定出了除 eIF5A 之外的两组受环吡酮和地拉罗司协调影响的蛋白质。第 1 组蛋白质（Hsp27、NM23 和 DJ-1）在翻译水平下调，而第 2 组蛋白质（TrpRS 和 PRDX2）在 mRNA 水平上调。进一步的研究证实，eIF5A 和 DOHH 是宫颈癌细胞中 Hsp27 表达所必需的，并且调控其关键靶标 IκB 和 NF-κB。我们的结果表明，成熟的 eIF5A 控制着一个名为 eIF5A 调控子的癌症驱动基因的翻译网络，在 mRNA 丰度和翻译水平上进行调控。在协调细胞增殖方面，eIF5A 调控子可以被环吡酮或地拉罗司等药物调节，这些药物可能被重新定位以控制癌细胞生长。
