Biomedical Sciences ETDs

Publication Date

5-1-2012

Abstract

Defining underlying molecular mechanisms exploited by cancer cells in their development and progression provides a necessary foundation for experimental therapeutics. The androgen receptor (AR) is a known therapeutic target for prostate cancer (CaP) given its well-established role in both the development and progression of CaP. The AR is a ligand activated transcription factor that regulates the expression of many genes involved in proliferation and differentiation. Identifying agents that down-regulate AR expression may elucidate mechanism(s) for selectively targeting the AR. Two related agents of the natural products curcumin and vitamin E, curcumin analog 27 (ca27) and alpha-tocopheryl quinone (TQ), respectively were identified that down-regulate AR protein expression in CaP cells. The purpose of this dissertation project was to identify molecular pathways that contribute to AR down-regulation mediated by ca27 and TQ. While both ca27 and TQ down-regulate the AR, the kinetics of AR down-regulation was distinct between the two agents. ca27s down-regulation of AR protein expression was observed within hours, while TQ effects were seen after two days. Despite this difference, ca27 and TQ were found to have many similarities in their mechanism of AR down-regulation. Both ca27 and TQ up-regulate CYP1A1 expression, a known aryl hydrocarbon receptor (AHR) regulated gene. The AHR is a ligand activated transcription factor known to be involved with detoxification and metabolic pathways. However, the AHR itself did not appear to be regulating the observed effects on AR expression mediated by ca27 and TQ. Interestingly, additional data suggests TQ might serve as a ligand for the AHR (Chapter 4). Further, ca27 and TQ down-regulation of AR protein expression was determined to be independent of proteasomal degradation and transcriptional inhibition. Due to chemical structure considerations of ca27 and TQ, their potential to modulate CaP cell reduction/oxidation parameters was examined. Both ca27 and TQ were shown to down-regulate AR protein expression through a cellular redox mechanism, which was attenuated by the presence of the antioxidant N-acetylcysteine (Chapter 2 and 3), respectively. This study identifies pathways critical to the mechanism of action of ca27- and TQ-mediated AR protein down-regulation in human CaP cells and demonstrates that these novel agents act though alterations in cellular redox.

Keywords

"androgen receptor, mechanism, ca27, vitamin E, alpha tocopherylquinone"

Sponsors

College of Pharmacy Department of Pharmaceutical Sciences, Pfizer Safety Scholar Fellowship, School of Medicine Department of Biochemistry and Molecular Biology

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Bisoffi, Marco

Second Advisor

Thompson, Todd

First Committee Member (Chair)

Marcus, Craig

Second Committee Member

Orland, Rob

Third Committee Member

Bologa, Cristian

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