title: Phosphatidylinositol 3'-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN.
abstract: OBJECTIVE
  Medulloblastomas represent the most frequent malignant brain tumors of childhood. They are supposed to originate from cerebellar neural precursor cells. Recently, it has been shown that Sonic Hedgehog-induced formation of medulloblastoma in an animal model is significantly enhanced by activation of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway.
  
  
  METHODS
  To examine a role for PI3K/AKT signaling in the molecular pathogenesis of human medulloblastoma, we did an immunohistochemical study of the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma samples: All samples displayed p-AKT expression. To investigate if an activated PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five human medulloblastoma cell lines with increasing concentrations of the PI3K inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The antiproliferative effect could be antagonized by overexpressing constitutively active AKT. As the activation of PI3K/AKT signaling may be associated with alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to frequent allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA expression.
  
  
  RESULTS
  Proliferation of all of the medulloblastoma cell lines was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss was detected in 16% of the cases. One medulloblastoma cell line was found to carry a truncating mutation in the PTEN coding sequence. Even more important, PTEN mRNA and protein levels were found to be significantly lower in medulloblastomas compared with normal cerebellar tissue of different developmental stages. Reduction of PTEN expression was found to be associated with PTEN promoter hypermethylation in 50% of the tumor samples.
  
  
  CONCLUSIONS
  We conclude that activation of the PI3K/AKT pathway constitutes an important step in the molecular pathogenesis of medulloblastoma and that dysregulation of PTEN may play a significant role in this context.
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Boris
authors.initials: B
authors.lastname: Digon-Söntgerath
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.forename: Anke
authors.initials: A
authors.lastname: Waha
authors.forename: Elmar
authors.initials: E
authors.lastname: Endl
authors.forename: Indra
authors.initials: I
authors.lastname: Dani
authors.forename: Dorota
authors.initials: D
authors.lastname: Denkhaus
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Goodyer
authors.forename: Niels
authors.initials: N
authors.lastname: Sörensen
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism*; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human