GSBS Dissertations and Theses

Approval Date

8-5-2016

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Biochemistry and Molecular Pharmacology

First Thesis Advisor

Alonzo Ross, PhD

Keywords

Glioblastoma, Apoptosis, DNA Repair, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Double-Stranded DNA Breaks, DNA Damage, Dacarbazine

Subjects

Dissertations, UMMS; Glioblastoma; Apoptosis; DNA Repair; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; DNA Breaks, Double-Stranded; DNA Damage; Dacarbazine

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

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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