DOI
https://doi.org/10.25772/00KK-GK42
Defense Date
2020
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Dr. David Gewirtz
Abstract
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although standard treatments such as androgen deprivation therapies (ADT) and antiandrogens have increased survival for many patients, most men placed on these therapies will develop castration-resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity and instead promote cell growth arrest. Our current work demonstrates that prostate tumor cells grown in the absence of androgens by using charcoal-stripped serum undergo senescence-mediated or senescent-like growth arrest, based on the cellular expression of senescence-associated-beta-galactosidase (SA-β-Gal). Our studies further suggest that this senescence is transient and “reversible,” as cells are able to resume proliferation once androgen deprivation is terminated. Enrichment for senescent cells by SA-β-Gal-based FACS (fluorescence assisted cell sorting) confirmed that ADT-induced senescent cells can recover their proliferative capacity. While the transient nature of this senescence arguably creates the potential risk for disease recurrence, the senescent state induced by ADT may also provide a therapeutic strategy that can be exploited through the use of senolytics such as ABT-263 following ADT-induced senescence. ABT-263 selectively drives senescent, ADT-treated cells into apoptotic cell death while having minimal effect on non-senescent cells. Ongoing studies are designed to phenotypically characterize the recovered senescent cells, to determine whether recovery from senescence promotes development of CRPC, and to what extent senolytics might delay the conversion from an ADT-sensitive to an ADT-resistant state.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-2-2020
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Medical Cell Biology Commons, Medical Pharmacology Commons