Date of Award
Doctor of Philosophy
Marc B. Cox
The androgen receptor complex plays an essential role in prostate cancer progression due to exploitation of the androgen receptor (AR) as a transcription factor. The final stage of the receptor complex consists of a dimerized receptor, a dimeric heat shock protein (Hsp90), the cochaperone p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and its ligand α dihydrotestosterone (DHT). While current treatments focus on blocking the androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone-refractory prostate cancer (HRPC).
Therefore, we have been interested in targeting other members of the androgen receptor complex and signaling cascade, namely the immunophilin FK506 Binding Protein 52 (FKBP52) and the cell signaling protein β-catenin. FKBP52 has the ability to potentiate activity of the androgen, progesterone, and glucocorticoid receptors and is a novel prostate cancer biomarker. β-catenin is a member of the cellular adhesion complex with E-cadherin in healthy cells, but in aberrant situations, β-catenin actively promotes cancer progression and invasion.
Our data in FKBP52 knockout mouse embryonic fibroblasts (52 KO MEF) and FKBP52 Knock down 22RV1 cell lines suggests that FKBP52 and β-catenin work in tandem to synergize AR transcriptional activity. When AR, FKBP52, and β-catenin are cotransfected, AR signaling synergizes under levels of very low DHT, as tracked by luciferase reporter assays. The synergy is so great that it dwarfs the potentiation of FKP52 and regulation of β-catenin alone. According to pull down assays, FKBP52 and β-catenin can bind in the absence of other proteins. Luciferase assays of mutant FKBP52 proteins suggest that FKBP52's binding to β-catenin involves the FKBP52 proline-rich loop but acts independently of Hsp90 binding. Interestingly, it appears that this synergistic effect is DNA sequence-specific, suggesting that the regulation by these proteins occurs at the transcriptional level. We have successfully abrogated the synergism of these proteins using a small molecule inhibitor compound MJC13, developed in our laboratory. According to surface plasmon resonance studies, this molecule binds the androgen receptor at the Binding Function 3 (BF-3) regulatory surface, the putative interaction surface for FKBP52 regulation of receptor. MJC13 potency is not improved with the combined administration of the anti-androgen Bicalutamide or the Hsp90 inhibitors KU174 or 17AAG. Studies in 22RV1 prostate cancer cells comparing control cells to FKBP52 knock down cells reveal the obligatory role of FKBP52 in β-catenin potentiation of AR. In the absence of FKBP52, β-catenin transfection barely increases AR signaling over basal levels, but when FKBP52 is present, β-catenin is a strong coactivator of transcription by AR. This information will lead to the development of new prostate cancer therapies.
Received from ProQuest
Cheryl Lynne Storer
Storer, Cheryl Lynne, "A Novel FKBP52/Β-Catenin Complex Specifically Regulates Androgen Receptor Activity" (2013). Open Access Theses & Dissertations. 1939.