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    The Role of Cellular and Viral Oncogenes in the Regulation of Hypoxia and Glucose Metabolism in Malignant Brain Tumors

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    Genre
    Thesis/Dissertation
    Date
    2011
    Author
    Noch, Evan K.
    Advisor
    Khalili, Kamel, 1951-
    Committee member
    Tuszynski, George P.
    Hu, Wenhui
    Safak, Mahmut
    Laterra, John
    Department
    Biomedical Neuroscience
    Subject
    Neurosciences
    Oncology
    Virology
    Aeg-1
    Glioblastoma
    Glucose Metabolism
    Glycolysis
    Hypoxia
    Jc Virus
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2022
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2004
    Abstract
    Glioblastomas continue to carry poor prognoses for patients despite advances in surgical, chemotherapeutic, and radiation regimens. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and elevated expression levels of hypoxia-inducible factor-1 á (HIF-1á). HIF-1á expression allows metabolic adaptation to low oxygen availability, partly through upregulation of vascular endothelial growth factor (VEGF) and increased tumor angiogenesis as well as induction of anaerobic glycolysis. In this study, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) by hypoxia in glioblastoma cells. AEG-1 has the capacity to promote anchorage-independent growth and cooperates with Ha-ras in malignant transformation. In addition, AEG-1 was recently demonstrated to serve as an oncogene and can induce angiogenesis and autophagy in glioblastoma. Results from in vitro studies show that hypoxic induction of AEG-1 is dependent on HIF-1á stabilization during hypoxia and that phosphatidylinositol 3-kinase (PI3K) inhibition abrogates AEG-1 induction during hypoxia through loss of HIF-1á stability. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) production prevents this induction. Additionally, AEG-1 knockdown results in increased ROS production and increased glucose deprivation-induced cytotoxicity, whereas AEG-1 overexpression prevents ROS production and decreases glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of cell stress. From studies examining the expression of enzymes involved in glucose metabolism, we demonstrate that AEG-1 alters the tumor metabolic profile in a partially 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Moreover, glycolytic inhibition modulates the metabolic effects induced by AEG-1, and AEG-1 knockdown reduces the growth and alters the metabolic phenotype of glioblastoma subcutaneous xenografts. These observations link AEG-1 overexpression observed in glioblastoma with hypoxia and glucose metabolic signaling, and targeting these physiological pathways may lead to therapeutic advances in the treatment of glioblastoma in the future. Recent studies have reported the detection of the human neurotropic virus, JC Virus (JCV), in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as â-catenin and IRS-1, play a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells that endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by AMPK, a critical sensor of the AMP/ATP ratio in cells. We have found that AMPK activation inhibits T-antigen expression, whereas AMPK inhibition prevents glucose deprivation-mediated T-antigen suppression. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen-expressing medulloblastoma cells, as compared to those which do not express T-antigen, exhibit less G1 arrest and an increased percentage of cells in the G2 phase of the cell cycle during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on ROS production during glucose deprivation. Additionally, studies indicate that T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. We have also found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamde (6-AN) and oxythiamine (OT). Enzyme expression studies also indicate that T-antigen upregulates the expression of the pentose phosphate enzyme, transaldolase-1 (TALDO1), demonstrating a potential link between T-antigen and glucose metabolic regulation. These studies highlight the potential involvement of JCV T-antigen in the proliferation and metabolic phenotype of medulloblastoma and may enhance our understanding of the role of viral proteins in tumor glycolytic metabolism, thus implicating these proteins as potential targets for the treatment of virus-associated tumors.
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