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    RARRES1 Modulation of Tubulin Deglutamylation Regulates Metabolism and Cell Survival

    Cover for RARRES1 Modulation of Tubulin Deglutamylation Regulates Metabolism and Cell Survival
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    View/Open: Maimouni_georgetown_0076D_14109.pdf (11.MB) Bookview

    Creator
    Maimouni, Sara
    Advisor
    Byers, Stephen W.
    ORCID
    https://orcid.org/0000-0002-6085-0766
    Abstract
    One of the driving mechanisms of cancer progression is the reprogramming of metabolic pathways in intermediary metabolism. Cancers increase their energy expenditure by increasing ATP production for utilization in anabolic pathways to increase production of proteins, nucleic acids and lipids. The Warburg Effect, where cancer cells predominantly use aerobic glycolysis rather than oxidative phosphorylation to produce ATP, was long thought to be the main initiating pathway in increasing tumor burden. However, compelling new evidence shows that there exists metabolic heterogeneity among and within tumors. Mitochondrial respiration often plays a major role in tumor progression, as many different cancers contain a subpopulation of slow-cycling tumor-initiating cells that are multidrug-resistant and dependent on oxidative phosphorylation. These cells represent a target for cancer therapy. However, the identification of endogenous regulators of mitochondrial respiration is understudied. Depletion of (RARRES1) occurs in many cancers, including melanoma, colon, prostate and breast cancers. Interestingly, in cancers associated with fibrosis, such as triple negative breast cancer, pancreatic and hepatocellular carcinomas, RARRES1 is overexpressed. Its role in metabolism might explain the duality of this protein in cancer. Our data show that RARRES1 and its target CCP2 regulate mitochondrial bioenergetics and subsequently alter energy homeostasis by modulating the function of the mitochondrial voltage-dependent anion channel (VDAC). The changes in energy homeostasis rewire glucose for biosynthetic pathways, such as de novo lipogenesis, that drive the pathogenicity and survival of cancer. These data lay the foundation for metabo-therapy of the many tumor types that exhibit RARRES1 depletion or overexpression and may have the added benefit of targeting drug-resistant tumor-initiating cells.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1053048
    Date Published
    2018
    Subject
    Cellular Metabolism; Metabolic Reporgramming in Tumor Biology; PPAR Signaling; RARRES1; Retinoic Acid Signaling; Cytology; Cellular biology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    200 leaves
    Collections
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility