title: Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis.
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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Manny D
authors.initials: MD
authors.lastname: Bacolod
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Alzubi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. pbfisher@vcu.edu.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt