title: Nonredundant functions for Akt isoforms in astrocyte growth and gliomagenesis in an orthotopic transplantation model.
abstract: 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 by using a model system driven by common glioma abnormalities, loss of function of p53 and Pten, and expression of EGFRvIII. Both Pten deletion and EGFRvIII expression 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, whereas 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 on 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.
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Raelene
authors.initials: R
authors.lastname: Endersby
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000209:etiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000032:analysis / Q000502:physiology; D005910:Glioma / Q000209:etiology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D007527:Isoenzymes; D016159:Tumor Suppressor Protein p53; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D013755:Tetradecanoylphorbol Acetate