Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 11, Pages 3421-3426Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414573112
Keywords
Akt; glioma; DNA repair; RCAS/tv-a mouse model
Categories
Funding
- NIH [CA141432, CA09850305, U24CA143835]
- MD Anderson Cancer Center core grant from the National Cancer Institute [CA16672]
- Goldhirsh Foundation
- Academy of Finland [132877, 259038]
- Sigrid Juselius Foundation
- Finnish Funding Agency for Technology and Innovation Finland Distinguished Professor program
- Odyssey Fellowship
- Academy of Finland (AKA) [259038, 259038] Funding Source: Academy of Finland (AKA)
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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.
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