Prostate cancer (PCa) is the second leading cause of mortality amongst U.S. men. PCa is initially androgen-dependent (AD) and anti-androgen therapy is effective in virtually all patients. Unfortunately, patients develop and eventually succumb to androgen-independent disease, at which point PCa tumors continue to grow and metastasize despite castrate levels of androgen. A growing body of evidence has established that sustained growth of Al PCa is dependent upon continued expression and activation of the androgen receptor (AR). Because the primary function of the AR is to serve as a transcription factor that binds to the androgen response element (ARE) in target genes that inhibit apoptosis and promote proliferation, we hypothesize that inhibition of the transcriptional activity of the AR will result in diminished growth of Al PCa. Our overall objective is to provide proof-of-principle evidence that inhibition of AR transcriptional activity by blocking the AR-ARE interaction will retard human Al PCa growth in vitro and in vivo. This evidence will be the basis for future studies to identify small molecule inhibitors of AR transcriptional activity by interfering with the AR-ARE interaction. Thus, our long-term objective is to develop a drug to specifically block AR transcriptional activity that could potentially be used to treat patients with Al prostate cancer. For the current application, our principal strategy to block binding of the AR to its cognate ARE involves the ectopic expression of a deletion mutant of the AR, which contains the AR DNA binding domain (DBD), but lacks both the transactivation domain (TAD) and ligand binding domain (LBD). We and others have shown that AR-DBD constructs have been shown to inhibit the transcriptional activity of the full-length AR. Using this strategy, we propose the following specific aims: 1) Establish that expression of the AR-DBD inhibits the transcriptional activity of the AR by preventing the AR-ARE interaction, and 2) Demonstrate that inhibition of the AR-ARE interaction results in reduced growth of Al PCa both in vitro and in vivo. ? ?
| Tai, Sheng; Sun, Yin; Liu, Nan et al. (2012) Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells. Mol Cancer Ther 11:1320-31 |
