期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3421-3426
DOI：10.1073/pnas.1414573112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGlioblastoma is the most common and aggressive type of glioma, with a median survival of 15 mo. A major obstacle to effective treatment is de novo or acquired resistance to standard-care therapies, including radiation and temozolomide. Enhanced DNA repair can allow damaged or mutated cells to survive, contributing to resistance and tumor recurrence. We have identified Akt3 as the dominant Akt isoform that robustly stimulates glioma progression. We also discovered key roles for Akt3 in activating DNA repair pathways, which led to enhanced survival of human glioblastoma cells following radiation or temozolomide treatment. Our work has potential broad application to multiple cancer types in which Akt3 is expressed. Blocking this pathway may help prevent or alleviate DNA repair-mediated therapeutic resistance. 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.
关键词：Akt ; glioma ; DNA repair ; RCAS/tv-a mouse model
