Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Dianzheng Zhang, PhD

Second Advisor

Ruth Borghaei, PhD

Third Advisor

Cathy Hatcher, PhD

Abstract

Prostate cancer (PCa) is an incredibly common disease in the United States, with approximately 170,000 new diagnoses and 30,000 deaths occurring on an annual basis. The current mainstay of treatment for PCa is known as androgen deprivation therapy (ADT), which has proven to be an effective short-term option in earlier stages of the disease. Unfortunately, longer periods of ADT risk accelerating progression of the cancer to the point where 25% of all treated patients relapse to an incurable, metastatic, and highly lethal form known as castration-resistant prostate cancer (CRPC). In approximately 60% of CRPC cases, a splice variant of androgen receptor called AR-V7 can be detected and has been shown to contribute to this progression. Recent studies have shown that resveratrol (RSV) is capable of increasing the polyubiquitination and subsequent proteasomal degradation of ARV7 proteins in CRPC cells, though the mechanism behind this effect remains unknown. To investigate the hypothesis that this may occur via downregulation of DBC1 proteins which normally blocks the polyubiquitination site on AR-V7, 22RV1 cells were cultured and treated with varying concentrations of RSV for up to 24 hours. Results showed that RSV post-transcriptionally downregulates levels of DBC1 while reducing levels of AR-V7 proteins and the expression of its target genes. N-cadherin, a known target gene of AR-V7, was also shown to be downregulated by RSV in a statistically significant and dose-dependent manner at the mRNA and protein levels. RSV was shown to simultaneously increase levels of E-cadherin proteins and mRNA in a statistically significant and dose-dependent manner, suggesting it may be capable of inhibiting or preventing the epithelial-to-mesenchymal transition (EMT) in CRPC cells. Together, these findings implicate RSV as a promising therapeutic option for the majority of CRPC patients who are ARV7- positive.

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