Thesis Format
Monograph
Degree
Master of Science
Program
Anatomy and Cell Biology
Supervisor
Penuela, Silvia
2nd Supervisor
Hebb, Matthew
Co-Supervisor
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive and fatal central nervous system tumor in adults. We sought to investigate the effects of targeting pannexin 1 (PANX1) as a novel strategy for GBM treatment interventions. PANX1 is a glycoprotein that forms heptameric channels facilitating ion and metabolite transport across cell membranes. Aberrant PANX1 overexpression has been associated with tumor-promoting properties in numerous cancer types. Here, we used bulk RNA-sequencing to show that PANX1 depletion from patient-derived GBM cells generated the differential expression of more than 2000 genes. Differentially expressed genes in PANX1-knockout GBM cells were primarily associated with cell movement and intercellular communication. Pharmacological PANX1 inhibition in GBM cells reduced cell growth and altered the appearance of filamentous actin. Our findings highlight potential molecular pathway connections to PANX1 in GBM and support the continued evaluation of disrupting PANX1 function as a potential GBM treatment to improve patient outcomes.
Summary for Lay Audience
Glioblastoma Multiforme (GBM) is a lethal brain cancer with a median life expectancy of less than two years. We propose a new potential approach to GBM treatment by targeting pannexin 1 (PANX1), a component in many human cell types that facilitates cell communication. PANX1 forms a large pore at the cell surface, facilitating the controlled release of molecules from the cell into the surrounding extracellular space that neighbouring cells can receive as communication signals. Accumulating data indicates that PANX1 exhibits tumor-promoting properties in numerous cancer types where the amount of PANX1 present is overabundant; however, the role of PANX1 in GBM has yet to be understood. Here, we report that GBM cells contain excessive PANX1 compared to non-neoplastic brain cells and investigate the mechanisms through which PANX1 overexpression may contribute to GBM using patient-derived GBM cells. To investigate the effects of deleting PANX1 from GBM cells, we determined which genes are expressed differently in the absence of PANX1. We found that deleting PANX1 from GBM cells substantially changed the expression of genes generating cellular components involved in intercellular communication and cell movement, critical cellular processes that are commonly altered in cancer cells. Blocking PANX1 channel function by treating GBM cells with Probenecid or Spironolactone, two Health Canada-approved pharmaceuticals, reduced GBM cell growth. We also observed that Probenecid and Spironolactone treatments disrupted the appearance of actin filaments, a scaffolding-like component of cells responsible for cell structure and migration. Overall, we uncovered new connections between various cellular components and PANX1 that may be critical in understanding the role of PANX1 in GBM and we demonstrate the potential for targeting PANX1 to impede GBM cell growth. Ultimately, our findings support the continued investigation of PANX1 as a potential therapeutic target for future GBM treatments, which used in conjunction with the current standard of care may help improve outcomes for patients with this devastating disease.
Recommended Citation
Van Kessel, Carlijn, "Investigating the Role of Pannexin 1 in Patient-Derived Glioblastoma Multiforme Cells" (2024). Electronic Thesis and Dissertation Repository. 10342.
https://ir.lib.uwo.ca/etd/10342
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