Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis.
Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis.
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DOI：
10.1158/0008-5472.can-13-2978
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Fisher PB
中科院分区：
文献类型：
--
作者：
Hu B;Emdad L;Bacolod MD;Kegelman TP;Shen XN;Alzubi MA;Das SK;Sarkar D;Fisher PB
癌基因AEG-1 （MTDH）在多形性胶质母细胞瘤（GBM）和许多其他类型的癌症中高度表达，在那里它激活多种信号通路，驱动增殖、侵袭、血管生成、化疗耐药、放射耐药和转移。AEG-1激活Akt信号通路，Akt和c-Myc是AEG-1转录的正调节因子，在AEG-1和Akt之间形成调节肿瘤发生的正反馈回路。在这里，我们描述了GBM细胞中AEG-1的内部结构域和Akt2的PH结构域之间的直接相互作用，Akt2是GBM的主要驱动因素。在GBM中，AEG-1和Akt2的表达和相互作用升高，参与肿瘤细胞的存活、增殖和侵袭。临床上，患者标本的基因表达和免疫组化分析显示，AEG-1和Akt2的表达与GBM进展和患者生存率降低相关。AEG-1-Akt2相互作用延长了Akt2在S474位点磷酸化的稳定性，调节下游信号级联，使细胞增殖和存活。通过Akt2-PH结构域的竞争性结合破坏AEG-1-Akt2相互作用导致细胞活力和侵袭性降低。当与AEG-1沉默相结合时，Akt2-PH的条件表达显着提高了人GBM原位小鼠模型的存活率。我们的研究揭示了AEG-1增强胶质瘤进展的一种新的分子机制，并为阻断AEG-1- akt2信号功能作为一种新的GBM治疗方法提供了理论依据。
The oncogene AEG-1 (MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades which enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment.