Akt2 and Akt3 play a pivotal role in malignant gliomas
Akt2 and Akt3 play a pivotal role in malignant gliomas
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DOI：
10.1093/neuonc/nop026
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发表时间：
2010-03-01
期刊：
影响因子：
15.9
通讯作者：
Nagahiro, Shinji
中科院分区：
文献类型：
--
作者：
Mure, Hideo;Matsuzaki, Kazuhito;Nagahiro, Shinji
Akt是磷脂酰肌醇3-激酶的主要下游效应子之一，在包括胶质母细胞瘤在内的多种癌症中过度表达和激活。然而，Akt亚型Akt 1/PKB α、Akt 2/PKB β和Akt 3/PKB γ的表达谱及其在恶性胶质瘤中的功能作用尚不清楚。因此，我们检测了人类星形细胞瘤组织中Akt亚型的蛋白质和mRNA表达模式。胶质母细胞瘤，和非肿瘤区域。我们还探讨了在恶性胶质瘤细胞中的生物学作用，使用RNA干扰介导的敲低和过表达的质粒DNA的每个亚型的Akt亚型。Akt 1蛋白和mRNA在胶质瘤和正常对照组织中的表达相似。Akt 2蛋白和mRNA表达水平随肿瘤病理分级的升高而升高，而Akt 3 mRNA和蛋白表达水平随肿瘤病理分级的升高而降低。在U87 MG、T98 G和TGB细胞中，通过RNA干扰下调Akt 2或Akt 3降低了Bad磷酸化形式的表达。导致半胱天冬酶依赖性细胞凋亡的诱导。Akt 1敲低不影响细胞生长或存活。我们首先证明了Akt 2或Akt 3的过表达下调了其他蛋白的表达，并且内源性Akt 3蛋白在U87 MG细胞中显示出高激酶活性。我们的数据表明，Akt 2和Akt 3在人恶性胶质瘤细胞的生存能力中起重要作用。靶向Akt 2和Akt 3可能有望治疗胶质瘤患者。
Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase., is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKB alpha, Akt2/PKB beta, and Akt3/PKB gamma and their functional roles in malignant glioma are not Well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas., glioblastomas., and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad., resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role In the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.