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    Characterization of the effects of IDH2 mutations and (R)-2-HG in cancer progression

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    Genre
    Thesis/Dissertation
    Date
    2015
    Author
    Kotredes, Kevin Patrick
    Advisor
    Gamero, Ana
    Committee member
    Gallucci, Stefania
    Hoffman, Barbara (Biochemist)
    Rogers, Thomas J., 1950-
    Shore, Scott K.
    Goldfinger, Lawrence
    Department
    Molecular Biology and Genetics
    Subject
    Biology, Molecular
    Genetics
    Biochemistry
    2-hydroxyglutarate
    Biomarker
    Cancer
    Glioblastoma
    Idh2
    Metabolism
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3137
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3119
    Abstract
    The isocitrate dehydrogenase (IDH) family of enzymes is central to cellular metabolism, catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and production of NADPH. Recently, cancer-associated heterozygous somatic mutations in family members IDH1 and IDH2 were discovered and present predominantly in glioblastoma multiforme and acute myeloid leukemia. The major consequence of these point mutations is the biochemical production of the ‘oncometabolite’ (R)-2-hydroxyglutarate [(R)-2-HG] from α-KG. Recent studies indicate that unalike mutations of IDH2 produce different intracellular levels of (R)-2-HG, suggesting that IDH2 mutations may differentially influence tumorigenesis. Contrasting clinical studies find IDH mutations to be associated either with increased metastatic potential, or higher survival and enhanced chemosensitivity probabilities. Nevertheless, these studies failed to indicate specifically which of the various IDH mutations were found in each of the patients’ tumors. This raises important questions as to whether specific IDH mutations contribute differently to tumorigenesis. In this study, specific IDH2 mutations were evaluated and compared for their chemosensitivity, tumorigenic activity, and production of (R)-2-HG- all notable determinants for their potential use as tumor biomarkers. Three individual clinically relevant IDH2 mutations (IDH2-R172K, -R172M, and -R140Q) or IDH2-WT were expressed in human U87MG glioblastoma cells. We observed distinct changes in cell morphology, proliferation, migration, invasion, anchorage-independent growth and response to chemotherapeutic agents. Differences in base-line activation of various stress pathways were also observed, lending a plausible explanation to the differing phenotypic outcomes. Interestingly, the variable levels of endogenous (R)-2-HG produced by the cell panel inversely correlated with their respective growth rates, implicating (R)-2-HG as a negative regulator of tumor growth. Indeed, treatment of tumor cell lines, expressing IDH2-WT, with exogenous (R)-2-HG induced a decrease in cell proliferation in a dose-dependent manner. When tested in vivo, treatment of tumor-bearing mice with (R)-2-HG significantly reduced tumor volume. These in vivo results complement the results of soft-agar colony forming assays, demonstrating again that (R)-2-HG inhibits tumor growth. In contrast, immortalized cells subjected to long-term (R)-2-HG treatment showed enhanced cell proliferation. Their response to (R)-2-HG, however, could be switched from growth promotion to that of growth inhibition through expression of oncogenic Ras. Thus, these findings demonstrate conclusively that IDH2 mutations are not alike and that oncometabolite (R)-2-HG plays dual roles in tumorigenesis.
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