title: Akt2 and Akt3 play a pivotal role in malignant gliomas.
abstract: 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/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma 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.
authors.affiliation: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan. gaudi0529@ybb.ne.jp
authors.forename: Hideo
authors.initials: H
authors.lastname: Mure
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Mizobuchi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Kageji
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002469:Cell Separation; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt