Genomically Amplified Akt3 Activates DNA Repair Pathway and Promotes Glioma Progression

Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3421-6. doi: 10.1073/pnas.1414573112. Epub 2015 Mar 3.

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.

Keywords: Akt; DNA repair; RCAS/tv-a mouse model; glioma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • DNA Damage / genetics
  • DNA Repair / drug effects
  • DNA Repair / genetics*
  • DNA Repair / radiation effects
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Disease Progression*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / radiation effects
  • Gene Amplification* / drug effects
  • Gene Amplification* / radiation effects
  • Gene Expression Regulation, Neoplastic
  • Genome, Human*
  • Glioma / enzymology
  • Glioma / genetics*
  • Glioma / pathology
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / chemistry
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation Tolerance / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects
  • Temozolomide
  • Transcription, Genetic

Substances

  • Isoenzymes
  • Dacarbazine
  • Proto-Oncogene Proteins c-akt
  • Temozolomide

Associated data

  • GEO/GSE66177