Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Kristen M. Turner, Youting Sun, Kirsi J. Granberg, Brady Bernard, Limei Hu, David E. Cogdell, Xinhui Zhou, Olli Yli-Harja, Matti Nykter, Ilya Shmulevich, WK Yung, Gregory N. Fuller, Wei Zhang

    Research output: Contribution to journalArticleScientificpeer-review

    64 Citations (Scopus)

    Abstract

    Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

    Original languageEnglish
    Pages (from-to)3421-3426
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume112
    Issue number11
    DOIs
    Publication statusPublished - 2015
    Publication typeA1 Journal article-refereed

    Keywords

    • Akt
    • DNA repair
    • Glioma
    • RCAS/tv-a mouse model

    Publication forum classification

    • Publication forum level 3

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