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Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis.
- Source :
-
Cancer research [Cancer Res] 2014 Dec 15; Vol. 74 (24), pp. 7321-32. Date of Electronic Publication: 2014 Oct 10. - Publication Year :
- 2014
-
Abstract
- The oncogene astrocyte elevated gene-1 (AEG-1; MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance, and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here, we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation, and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades that enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Adhesion Molecules metabolism
Cell Line, Tumor
Cell Proliferation genetics
Cell Survival genetics
Gene Expression Regulation, Neoplastic
Glioblastoma metabolism
Glioblastoma pathology
Glioma metabolism
Glioma pathology
Humans
Membrane Proteins
Mice
Neovascularization, Pathologic genetics
Protein Interaction Maps genetics
Proto-Oncogene Proteins c-akt metabolism
RNA-Binding Proteins
Signal Transduction genetics
Cell Adhesion Molecules genetics
Glioblastoma genetics
Glioma genetics
Proto-Oncogene Proteins c-akt biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 74
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 25304263
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-13-2978