Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3
Abstract
Our operating hypothesis is that checkpoint suppressor 1 (CHES1)/FOXN3 is an androgen withdrawal-induced gene that promotes prostate cancer (CaP) resistance to apoptosis. The purposes of this research are two-fold. The first is to define the mechanisms of CHES1 gene expression regulation and function, particularly in mediating apoptosis resistance during androgen ablation. Secondly, the tools yielded from our functional studies will be utilized to test the efficacy of CHES1-silencing therapy (CST) in preventing castration-resistant prostate cancer (CRPC) and to develop a mechanism-based noninvasive imaging strategy for monitoring the success of CST. Several significant findings were made. We defined the mechanisms through which CHES1 coordinates anti-apoptotic pathways, specifically by enhanced P13K/Akt activation and direct suppression of pro-apoptotic BNIP3 expression. Conversely, p53-mediated CHES1 down-regulation is regulated is required for genotoxic stress to trigger apoptosis. Another critical finding is that while CHES1 directly interacts with the AR, which can figure prominently in influencing CaP progression to CRPC, since our findings demonstrated that while CHES1 potently inhibits transcriptional activity of wild-type AR, it enhanced the activity of constititively-active AR splice variants associated with CRPC. Taken together, our findings provide strong support for exploiting CHES1 as a therapeutic target in that CHES1 antagonism would potentially lead to decreased anti-apoptotic P13K-Akt signaling, reinstatement of pro-apoptotic gene expression (i.e., BNIP3), and reduced activity of oncogenic AR splice variants.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA547340
Entities
People
- Clifford G Tepper
Organizations
- University of California