Nonredundant functions for Akt isoforms in astrocyte growth and gliomagenesis in an orthotopic transplantation model.
Nonredundant functions for Akt isoforms in astrocyte growth and gliomagenesis in an orthotopic transplantation model.
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DOI：
10.1158/0008-5472.can-10-3597
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Baker SJ
中科院分区：
文献类型：
--
作者：
Endersby R;Zhu X;Hay N;Ellison DW;Baker SJ
AKT家族包括三种高度同源的激酶，是PTEN/PI 3 K途径的必需介质，其在许多人类癌症中被失调。缺乏对正常和疾病组织中每种亚型的特异性活性的透彻理解。我们使用由常见胶质瘤异常、p53和Pten功能丧失以及EGFRvIII表达驱动的模型系统，评估了每个Akt亚型在胶质瘤形成中的作用。Pten缺失和EGFRvIII表达均加速p53缺失的原代鼠星形胶质细胞的增殖。所有三种Akt亚型在星形胶质细胞中表达和磷酸化，在Pten-null细胞中具有显著更高的活化。尽管在许多情况下，当单个Akt亚型被抑制时，会有大量的补偿，但也发现了亚型特异性效应。具体而言，Akt 1或Akt 2的丢失降低了Pten野生型星形胶质细胞的增殖，而需要多种亚型的联合丢失来抑制Pten无效星形胶质细胞的增殖。此外，Akt 3是转化星形胶质细胞和人脑胶质瘤细胞锚定非依赖性生长所必需的，Akt 3缺失抑制转化星形胶质细胞的侵袭。EGFRvIII表达转化了p53缺失的星形胶质细胞，有或没有Pten缺失，导致颅内移植后快速发展为高级别星形胶质细胞瘤。此外，表达EGFRvIII的Pten;p53-null星形胶质细胞的肿瘤发生被Akt 1损失延迟，并被Akt 2损失加速。总之，这些结果表明，上下文依赖的作用，为个别Akt亚型，并表明可能有异质性肿瘤反应亚型特异性抑制剂。
The AKT family, comprising three highly homologous kinases, is an essential mediator of the PTEN/PI3K pathway, which is deregulated in many human cancers. A thorough understanding of the specific activities of each isoform in normal and disease tissues is lacking. We evaluated the role of each Akt isoform in gliomagenesis using a model system driven by common glioma abnormalities, loss of function of p53 and Pten, and expression of EGFRvIII. Pten deletion and EGFRvIII expression both accelerated the proliferation of p53-null primary murine astrocytes. All three Akt isoforms were expressed and phosphorylated in astrocytes, with significantly higher activation in Pten-null cells. Despite substantial compensation in many contexts when individual Akt isoforms were inhibited, isoform-specific effects were also identified. Specifically, loss of Akt1 or Akt2 decreased proliferation of Pten wild-type astrocytes, while combined loss of multiple isoforms was needed to inhibit proliferation of Pten-null astrocytes. In addition, Akt3 was required for anchorage-independent growth of transformed astrocytes and human glioma cells, and Akt3 loss inhibited invasion of transformed astrocytes. EGFRvIII expression transformed p53-null astrocytes with or without Pten deletion, causing rapid development of high-grade astrocytoma upon intracranial transplantation. Furthermore, tumorigenesis of Pten;p53-null astrocytes expressing EGFRvIII was delayed by Akt1 loss and accelerated by Akt2 loss. Taken together, these results indicate context-dependent roles for individual Akt isoforms and suggest that there may be heterogeneous tumor response to isoform-specific inhibitors.