Date of Award

Winter 12-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Therapeutic resistance is a hallmark of glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults. Ionizing radiation (IR) has long been used to treat GBM. Despite advances in the methods of radiation delivery, radiation therapy only delays recurrence and is not curative. Furthermore, studies have shown that IR can induce adaptive responses that may enhance therapeutic resistance. Through in vitro studies of GBM cell culture models, we found that IR can induce the endoplasmic reticulum stress response (ERSR), and that the ERSR can mediate pro-survival signaling in the context of radiation therapy. In this dissertation, we identify the ATF6 and PERK pathways of the ERSR as important contributors to the viability of irradiated GBM cells. In addition, we elucidated a pro-survival function of plasma membrane associated GRP78, a major effector of ATF6, in GBM cells.

Our study began with a characterization of the link between IR and ER homeostasis. We found that IR could alter the oxidation status within the ER and could promote ER membrane expansion in a reactive oxygen species (ROS) dependent manner. This, together with observations of GRP78 induction by IR, suggested that IR could induce the ERSR. To test this hypothesis, we analyzed gene expression in irradiated GBM cells and found upregulation of genes downstream of ATF6, IRE1 and PERK – the three major pathways of the ERSR. Radiation induction of GRP78 required ATF6 expression, and silencing ATF6 resulted in reduced cell viability and increased sensitivity to IR. We also identified NOTCH1 as a novel potential downstream transcriptional target of ATF6, which suggests crosstalk between the ERSR and another major pro-survival pathway during the radiation response. Silencing ATF4, which is downstream of PERK, resulted in attenuated cell viability. However, we also found that IR could potentiate the effect of chemical inducers of ER stress and promote cell death in a PERK dependent manner. These opposing phenotypes suggest a dual function for PERK in modulating GBM cell viability.

To investigate the contributions of downstream effector of ERSR, GRP78, to cell viability, we treated GBM cells with antibodies against GRP78. Antibody binding to surface GRP78 was associated with reduced Akt phosphorylation, attenuation of mTOR pathway signaling, and enhanced radiation-induced cell death. Together, these findings highlight the dynamic potential for the ERSR to mediate GBM cell survival and adaptation to therapy. Further characterization of the ERSR in recurrent GBM may reveal new molecular targets to enhance therapeutic efficacy and further improve patient survival.


English (en)

Chair and Committee

Dennis Hallahan

Committee Members

Albert Kim, Andrei Laszlo, Joshua Rubin, Fumihiko Urano, Katherine Weilbaecher


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