Targeting the eIF4F translation initiation complex for cancer therapy
Targeting the eIF4F translation initiation complex for cancer therapy
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DOI：
10.4161/cc.7.16.6464
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发表时间：
2008-08-15
期刊：
影响因子：
4.3
通讯作者：
Graff, Jeremy R.
中科院分区：
文献类型：
--
作者：
Konicek, Bruce W.;Dumstorf, Chad A.;Graff, Jeremy R.
在多种人类癌症中，真核生物翻译起始因子4 E（eIF 4 E）的功能升高，并与疾病进展直接相关。实验模型中eIF 4 E的过度表达或过度活化可驱动细胞转化和恶性进展。升高的eIF 4 E功能触发eIF 4F翻译起始复合物的增强组装，从而驱动帽依赖性翻译。尽管所有加帽的mRNA都需要eIF 4F进行翻译，但mRNA库异常依赖于升高的eIF 4F翻译活性，从而选择性地和不成比例地受到改变的eIF 4F活性的影响。这些mRNA编码在恶性肿瘤的所有方面发挥重要作用的蛋白质，包括血管生成因子（VEGF、FGF 2）、癌蛋白（c-myc、细胞周期蛋白D1、ODC）、促存活蛋白（生存素、BCL-2）和参与肿瘤侵袭和转移的蛋白质（MMP-9、乙酰肝素酶）。靶向eIF 4F复合物的最新进展突出了该复合物在肿瘤细胞存活和血管生成中的作用，并阐明了肿瘤细胞对eIF 4F复合物抑制的敏感性增强。这些研究已经证明了靶向eIF 4 E和eIF 4F翻译起始复合物用于癌症治疗的吸引力和可行性，并促使第一种eIF 4 E特异性治疗进入临床。
In multiple human cancers, the function of the eukaryotic translation initiation factor 4E (eIF4E) is elevated and directly related to disease progression. Overexpression or hyperactivation of eIF4E in experimental models can drive cellular transformation and malignant progression. Elevated eIF4E function triggers enhanced assembly of the eIF4F translation initiation complex and thereby drives cap-dependent translation. Though all capped mRNAs require eIF4F for translation, a pool of mRNAs are exceptionally dependent on elevated eIF4F activity for translation and are thereby selectively and disproportionately affected by altered eIF4F activity. These mRNAs encode proteins that play significant roles in all aspects of malignancy including angiogenesis factors (VEGF, FGF2), onco-proteins (c-myc, cyclin D1, ODC), pro-survival proteins (survivin, BCL-2) and proteins involved in tumor invasion and metastasis (MMP-9, heparanase). Recent advances in targeting the eIF4F complex have highlighted the role for this complex in tumor cell survival and angiogenesis and have illuminated the enhanced susceptibility of the tumor cells to inhibition of the eIF4F complex. These studies have demonstrated the attractiveness and plausibility of targeting eIF4E and the eIF4F translation initiation complex for cancer therapy and have prompted the advance of the first eIF4E-specific therapy to the clinic.