The Role of the Co-Chaperone, CHIP, in Androgen Independent Prostate Cancer
Abstract
Expression of Chip, a Co-Chaperone Which Interacts with the Androgen Receptor, Results in Loss of AR Expression and Growth Inhibition of Prostate Cancer Cells Waleed Hassen, Xiaoyoung Zheng, Antonio Otero, Erwin Wang, Yuancheng Wang, Sherwin Zargaroff, Jian Pu, Mary Kunjappu, Avrom Caplan and Simon Hall Mount Sinai School of Medicine, New York Introduction and Objectives: Earlier studies in our laboratory and others have demonstrated that over-expression of a co-chaperone, CHIP, an E3 ligase which interacts with HSP-70/90, results in degradation of the androgen receptor (AR) (Cardozo et al, Arch Biochem Biophy, 2003 and He et al, JBC, 2004) Furthermore, it has been shown that CHIP binds directly to a highly conserved sequence on the AR to facilitate degradation. Mutations in this sequence are commonly identified in hormone refractory cancers from TRAMP mice (He et al, JBC, 2004), which result in prostate cancers when over-expressed in a transgenic model (Han et al, PNAS 2005). This suggests that CHIP may have important functions in the homeostatic mechanisms underlying AR function in prostate cancer. These studies explored the outcomes of CHIP over-expression in prostate cancer cells. Methods: CHIP over-expression was achieved by either lipofectamine or adenovirus mediated transduction; the latter contained a tetracycline control mechanism (tet-off). Studies first focused on AR levels by Western blot and effects on growth by either cell counts or MTT assays. Reduction in AR function was addressed by hormone binding studies, while the mechanism of growth suppression was detected by ascertaining cell cycle status via proprium iodide and FACS analysis. Results: By either method, CHIP over-expression resulted in both reduced levels of AR and growth suppression of only AR-expressing cells. Hormone binding studies in AR expressing cells noted reduced levels of hormone binding following CHIP over-expression, correlating with the reduced levels noted by Western blot.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2008
- Accession Number
- ADA490397
Entities
People
- Waleed A. Hassen
Organizations
- Icahn School of Medicine at Mount Sinai