AEG-1 overexpression is essential for maintenance of malignant state in human AML cells via up-regulation of Akt1 mediated by AURKA activation
AEG-1 overexpression is essential for maintenance of malignant state in human AML cells via up-regulation of Akt1 mediated by AURKA activation
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AEG-1 过表达对于通过 AURKA 激活介导的 Akt1 上调维持人类 AML 细胞的恶性状态至关重要
DOI：
10.1016/j.cellsig.2013.03.001
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发表时间：
2013-06-01
影响因子：
4.8
通讯作者：
Zhang, Huizhong
中科院分区：
文献类型：
--
作者：
Long, Min;Hao, Miaowang;Zhang, Huizhong
急性髓性白血病（AML）仍然具有高度致命性，这突出了对信号通路的更好理解的需要，这可以导致开发针对不同AML亚型共有的共同分子通路的新治疗方案。在这里，我们证明，星形胶质细胞升高基因-1（AEG-1）是这样的途径之一，参与细胞周期和凋亡的调节，并有助于增强HL-60和U937 AML细胞的增殖和化疗耐药性。AEG-1对AML的多效性作用与两个新的靶基因Aurora激酶A（AURKA）和Akt1相关。通过短发夹RNA（short-hairpin RNA，shRNA）下调AEG-1不仅可以在mRNA和蛋白水平上降低AURKA的表达，还可以降低磷酸化Akt的活性形式pAkt473和pAkt308的水平，与使用AURKA抑制剂Tozasertib（VX 680）的效果相似。此外，AEG-1 shRNA诱导的恶性表型变化可以通过AURKA的强制过表达通过增加AML细胞中的Akt1活化和磷酸化来减轻。另一方面，虽然AEG-1的外源性表达可以增加AURKA和Akt表达水平，但同时使用AURKA抑制剂Tozasertib阻断了AEG-1上调ECV304细胞中Akt表达的作用，表明AURKA可能是AEG-1调节Akt活化的关键介质，也是AEG-1维持AML恶性状态的关键效应子。此外，敲低AEG-1表达也改变了PTEN、生存素和stathmin的表达水平，这些基因已被报道参与了其他几种恶性肿瘤的发展。我们的研究结果为AEG-1在AML中的致癌作用提供了证据，并揭示了AEG-1和AURKA对Akt1激活的新功能联系。AEG-1可以作为AURKA信号通路中的药物设计靶点，用于更特异性地杀死AML细胞，同时保留正常细胞。(C)2013 Elsevier Inc. All rights reserved.
Acute myeloid leukemia (AML) remains highly fatal, highlighting the need for improved understanding of signal pathways that can lead to the development of new therapeutic regimens targeting common molecular pathways shared across different AML subtypes. Here we demonstrate that astrocyte elevated gene-1 (AEG-1) is one of such pathways, involving in cell cycle and apoptosis regulation and contributing to enhanced proliferation and chemoresistance in HL-60 and U937 AML cells. The pleiotropic effects of AEG-1 on AML were found to correlate with two novel target genes, Aurora kinase A (AURKA) and Akt1. Down-regulation of AEG-1 by short-hairpin RNA (shRNA) could not only decrease AURKA expression both on mRNA and protein levels but also decrease the levels of pAkt473 and pAkt308 (the active forms of phosphotylated Akt), similar effect as using AURKA inhibitor Tozasertib (VX680). Furthermore, the AEG-1 shRNA-induced malignant phenotype changes could be mitigated by forced overexpression of AURKA through increased Akt1 activation and phosphorylation in AML cells. On the other hand, although exogenous expression of AEG-1 could increase both AURKA and Akt expression levels the simultaneous use of AURKA inhibitor Tozasertib blocked AEG-1's role of up-regulation of Akt expression in ECV304 cells, suggesting that AURKA might be a key mediator of AEG-1 in regulating Akt activation, and a key effector of AEG-1 in maintaining the malignant state of AML. Moreover, knockdown AEG-1 expression also changed the expression levels of PTEN, survivin and stathmin, the genes that have been reported to be involved in the development of several other malignant tumors. Our results provide evidence for AEG-1's carcinogenesis role in AML and reveal a novel functional link between AEG-1 and AURKA on Akt1 activation. AEG-1 can be an important candidate as a drug design target within AURKA signal pathway for more specific killing of AML cells while sparing normal cells. (C) 2013 Elsevier Inc. All rights reserved.