Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Istinye University, Istanbul, Turkey.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
J Mol Med (Berl). 2020 Jun;98(6):775-787. doi: 10.1007/s00109-020-01917-8. Epub 2020 May 7.
Eukaryotic elongation factor-2 kinase (eEF2K), an atypical member of alpha-kinase family, is highly overexpressed in breast, pancreatic, brain, and lung cancers, and associated with poor survival in patients. eEF2K promotes cell proliferation, survival, and aggressive tumor characteristics, leading to tumor growth and progression. While initial studies indicated that eEF2K acts as a negative regulator of protein synthesis by suppressing peptide elongation phase, later studies demonstrated that it has multiple functions and promotes cell cycle, angiogenesis, migration, and invasion as well as induction of epithelial-mesenchymal transition through induction of integrin β1, SRC/FAK, PI3K/AKT, cyclin D1, VEGF, ZEB1, Snail, and MMP-2. Under stress conditions such as hypoxia and metabolic distress, eEF2K is activated by several signaling pathways and slows down protein synthesis and helping cells to save energy and survive. In vivo therapeutic targeting of eEF2K by genetic methods inhibits tumor growth in various tumor models, validating it as a potential molecular target. Recent studies suggest that eEF2K plays a role in tumor microenvironment cells by monocyte chemoattractant protein-1 (MCP-1) and accumulation of tumor-associated macrophages. Due to its clinical significance and the pivotal role in tumorigenesis and progression, eEF2K is considered as an important therapeutic target in solid tumors. However, currently, there is no specific and potent inhibitor for translation into clinical studies. Here, we aim to systematically review current knowledge regarding eEF2K in tumor biology, microenvironment, and development of eEF2K targeted inhibitors and therapeutics.
真核延伸因子-2 激酶（eEF2K）是一种α-激酶家族的非典型成员，在乳腺癌、胰腺癌、脑癌和肺癌中高度过表达，并与患者的不良生存相关。eEF2K 促进细胞增殖、存活和侵袭性肿瘤特征，导致肿瘤生长和进展。虽然最初的研究表明 eEF2K 通过抑制肽延伸阶段来充当蛋白质合成的负调节剂，但后来的研究表明它具有多种功能，并通过诱导整合素 β1、 SRC/FAK、PI3K/AKT、细胞周期蛋白 D1、VEGF、ZEB1、Snail 和 MMP-2 来促进细胞周期、血管生成、迁移和侵袭以及上皮-间充质转化的诱导。在缺氧和代谢窘迫等应激条件下，eEF2K 被多种信号通路激活，从而减缓蛋白质合成并帮助细胞节省能量和存活。通过遗传方法对 eEF2K 进行体内治疗靶向抑制了各种肿瘤模型中的肿瘤生长，验证了它作为潜在分子靶标的作用。最近的研究表明，eEF2K 通过单核细胞趋化蛋白-1（MCP-1）和肿瘤相关巨噬细胞的积累在肿瘤微环境细胞中发挥作用。由于其临床意义及其在肿瘤发生和进展中的关键作用，eEF2K 被认为是实体瘤中的一个重要治疗靶点。然而，目前尚无用于转化为临床研究的特异性和强效抑制剂。在这里，我们旨在系统地综述 eEF2K 在肿瘤生物学、微环境以及开发 eEF2K 靶向抑制剂和治疗方法方面的最新知识。
