Date of Award

2023

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

Abstract

Gliomas, which are tumors of any number of glial cell types in the brain or spinal cord, can be malignant or benign. They represent approximately 33% of all central nervous system tumors. Glioblastoma multiforme (GBM) is a fatal, grade 4 glioma, that accounts for nearly 14.5% of all central nervous system tumors. Current treatment options for GBM, however, remain ineffective, with the median survival period following diagnosis being only 15 months. Thus, there is an urgent and unmet need for the development of novel therapeutics for the treatment of GBM and other gliomas. Previously, our laboratory showed that testosterone, conjugated to bovine serum albumin (T-BSA), increased the sensitivity of rat C6 glioma cells to the mixed oxidative and metabolic insult, iodoacetic acid (IAA). Given that T-BSA does not readily cross the plasma membrane, we interpreted that this effect was a consequence of binding to a “receptor” on the plasma membrane. We thus referred to this entity as the putative membrane androgen receptor (mAR). Given that binding to this mAR increased cell death, we proposed that exploitation of this novel mechanism could enhance the efficacy of chemotherapeutics. However, a major limitation to translating our prior discovery to developing novel glioma therapeutics is the lack of understanding of the molecular identity of the mAR. Based on work conducted by our laboratory in evaluating the efficacy of sigma-2 receptor-active compounds, and the recent literature that hypothesizes the “molecular makeup” of the sigma-2 receptor, we hypothesized that the mAR consists of PGRMC1 and transmembrane protein 97 (TMEM97). Furthermore, our working model predicts that PGRMC1 and/or TMEM97 expression positively correlates with the efficacy of T-BSA in augmenting cytotoxicity, and further, that reduced expression of either PGRMC1 or TMEM97 will reduce the efficacy of T-BSA. To test our hypothesis, we proposed two specific aims. First, we evaluated the expression of PGRMC1 and TMEM97 in the C6 and other cellular/in vivo models of glioma (including models of glioblastoma), in which we have evaluated the efficacy of T-BSA and determine if the expression of PGRMC1 and TMEM97 correlates with the efficacy of T-BSA. In Aim 2, determined whether siRNA-mediated knockdown of either or both of these genes diminishes the efficacy of T-BSA in enhancing the cytotoxicity of IAA. The data obtained from this study have provided insight into the identity of the putative membrane androgen receptor, and have also paved the way for future studies aiming at specifically targeting and promoting cell death in glioma cells. Accordingly, these data implicate a novel, and potentially druggable target to improve the efficacy of chemotherapy drugs used to treat such gliomas that include glioblastoma multiforme.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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