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Author ORCID Identifier
https://orcid.org/0009-0001-8611-7677
Date Available
10-5-2028
Year of Publication
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
Faculty
Luksana Chaiswing
Faculty
Kate Zaytseva
Abstract
Radiotherapy (RT) is a primary treatment for prostate cancer (PCa), yet recurrent tumors may develop radioresistance. Here, we investigated mitochondrial adaptations in radioresistant PCa and whether targeting them could improve RT efficacy. Post-RT patient tissues showed increased mitochondrial biogenesis and antioxidant markers. Compared with parental cells, radioresistant PCa cells exhibited reduced RT sensitivity, increased mitochondrial content and respiration, and elevated basal reactive oxygen species (ROS) despite increased antioxidant defenses. Stable isotope-resolved metabolomics (SIRM) revealed altered mitochondrial metabolism in radioresistant PC3 cells. We then tested AuPhos-89, a mitochondria-localizing compound that increases mitochondrial ROS and disrupts ATP synthesis. AuPhos-89 increased mitochondrial hydrogen peroxide, decreased proteins involved in mitochondrial biogenesis and metabolism, and reduced measured TCA-cycle metabolite isotopologue abundances in three-dimensional PC3 spheroids. Transcriptomic analysis showed that AuPhos-89 contrasted RT-associated mitochondrial, redox, hypoxic, and inflammatory programs. In immunocompetent mice bearing radioresistant PCa allografts, AuPhos-89 reduced tumor growth, and its combination with RT was more effective than either treatment alone. Radioresistant PCa cells displayed enhanced growth under hypoxia. Although hypoxia attenuated several RT-associated oxidative effects, AuPhos-89 maintained hydrogen peroxide induction, TFAM suppression, and respiratory inhibition. Together, these findings support mitochondrial metabolism, redox homeostasis, and biogenesis as targets for improving RT efficacy in radioresistant PCa.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.449
Archival?
Archival
Funding Information
This dissertation research was supported by a National Cancer Institute diversity supplement (R01CA251663-02) awarded in 2023
Recommended Citation
Guerrier, Kahleel E., "Exploiting Mitochondrial Biogenetic, Metabolic, and Redox Homeostasis Adaptations in Radiation-Resistant Prostate Cancer Enhances Radiotherapy Efficacy" (2026). University of Kentucky Doctoral Dissertations. 883.
https://uknowledge.uky.edu/gradschool_diss/883
Supplementary SIRM data workbook
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