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    Exploiting DNA Repair and ER Stress Response Pathways to Induce Apoptosis in Glioblastoma Multiforme: A Dissertation

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    Authors
    Weatherbee, Jessica L.
    Faculty Advisor
    Alonzo Ross, PhD
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Biochemistry and Molecular Pharmacology
    Document Type
    Doctoral Dissertation
    Publication Date
    2016-08-05
    Keywords
    Dissertations, UMMS
    Glioblastoma
    Apoptosis
    DNA Repair
    Endoplasmic Reticulum
    Endoplasmic Reticulum Stress
    DNA Breaks, Double-Stranded
    DNA Damage
    Dacarbazine
    Glioblastoma
    Apoptosis
    DNA Repair
    Endoplasmic Reticulum
    Endoplasmic Reticulum Stress
    Double-Stranded DNA Breaks
    DNA Damage
    Dacarbazine
    Cancer Biology
    Cellular and Molecular Physiology
    Neoplasms
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    Abstract
    Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we reasoned that DSBs occurring during heightened ER stress would be deleterious. Treatment of GBM cells with TMZ+JLK1486 decreased cell viability and increased cell death due to apoptosis. We found that TMZ+JLK1486 prolonged ER stress induction, as indicated by elevated ER stress marker BiP, ATF4, and CHOP, while sustaining activation of the DNA damage response pathway. This combination produced unresolved DNA DSBs due to RAD51 reduction, a key DNA repair factor. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between ER stress and DNA repair pathways.
    DOI
    10.13028/M2V30X
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32240
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2V30X
    Scopus Count
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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