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Novel mechanisms of androgen receptor degradation by alpha-tocopherylquinone and curcumin analog 27

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/20817

Novel mechanisms of androgen receptor degradation by alpha-tocopherylquinone and curcumin analog 27

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Title: Novel mechanisms of androgen receptor degradation by alpha-tocopherylquinone and curcumin analog 27
Author: Fajardo, Alexandra
Advisor(s): Bisoffi, Marco
Thompson, Todd
Committee Member(s): Marcus, Craig
Orland, Rob
Bologa, Cristian
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): androgen receptor, mechanism, ca27, vitamin E, alpha tocopherylquinone
LC Subject(s): Androgens--Receptors.
Androgens--Pathophysiology.
Vitamin E--Therapeutic use.
Quinone--Therapeutic use.
Turmeric--Therapeutic use.
Prostate--Cancer--Chemical therapy.
Degree Level: Doctoral
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. ca27’s 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.
Graduation Date: May 2012
URI: http://hdl.handle.net/1928/20817

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