Exploiting DNA Repair and ER Stress Response Pathways to Induce Apoptosis in Glioblastoma Multiforme: A Dissertation
Authors
Weatherbee, Jessica L.Faculty Advisor
Alonzo Ross, PhDAcademic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
Biochemistry and Molecular PharmacologyDocument Type
Doctoral DissertationPublication Date
2016-08-05Keywords
Dissertations, UMMSGlioblastoma
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
Metadata
Show full item recordAbstract
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/M2V30XPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32240Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2V30X