Thesis
Small molecule Sigma1 modulators induce the degradation of androgen receptor and splice variants in castration resistant prostate cancer cells
Master of Science (M.S.), Drexel University
Apr 2015
DOI:
https://doi.org/10.17918/etd-7165
Abstract
Androgen receptor (AR) signaling is the primary driver for prostate cancer progression. Androgen deprivation therapy (ADT) although initially effective, will eventually fail with the development of castration resistant prostate cancer (CRPC), which is reflected by a restoration of AR activity. One way that patients develop CRPC is through constitutively active AR splice variants (ARVs). Theses ARVs can promote AR activity independent of androgen and are non-responsive to current AR axis inhibitors due to the lack of the ligand binding domain (LBD). Sigma1 is a unique ligand-operated scaffolding protein. It is highly expressed in cancer cells including prostate cancer cells, and plays an important role in cancer cell protein homeostasis including protein translation, folding, transport, and degradation. Our previous studies have shown that a small molecule Sigma1 modulator induces the degradation of full-length AR, suppresses its transcriptional activity and prevents the DHT-induced AR nuclear translocation. In this study, we first confirmed that the Sigma1 modulator can also reduce ARVs in CRPC cell lines and further demonstrated that the Sigma1 modulator induced degradation of ARVs is mediated by the ubiquitin proteasome system. Next, we compared the protein degradation profile mediated by the Sigma1 modulator with that of an inhibitor for HSP90, a well-defined AR chaperone protein. It was found that the Sigma1 modulator and HSP90 inhibitor engage with some overlapping but also distinct client proteins, indicating the differences in mechanisms governing the actions of HSP90 and Sigma1. Finally, we combined docetaxel, a standard treatment for CRPC patients, with a drug-like version of the Sigma1 modulator to synergistically suppress CRPC cell colony formation using the Chou-Talalay method to assess the drug combination effect. Collectively, this study shows that the Sigma1 modulator can induce the degradations of AR and ARVs in CRPC cell lines and will support the development of potential novel therapeutics to counter the resistance to current AR signaling inhibitors mediated by ARVs.
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Details
- Title
- Small molecule Sigma1 modulators induce the degradation of androgen receptor and splice variants in castration resistant prostate cancer cells
- Creators
- Nan Chen - DU
- Contributors
- Felix J. Kim (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 7165; 991014632511904721