The Role of the Co-Chaperone, CHIP, in Androgen-Independent Prostate Cancer
Abstract
Androgen ablation, or androgen deprivation therapy (ADT), is the mainstay of treatment for patients with locally advanced or metastatic prostate cancer. This therapy is only temporizing, however, and within 3-4 years the vast majority of patients develop androgen independent prostate cancer (AIPC). Once a patient develops AIPC, treatment options are limited and less effective, with first line treatment providing only 13-15 month survival. This seminal event in disease progression has been the subject of much research, and while many factors are likely to be involved, the androgen receptor (AR) has been found to play a pivotal role in both the development and maintenance of AIPC. Many changes in the AR have been described, including mutation, constitutive activation and changes in expression levels. Like all receptors, AR's tertiary structure is critical to its function. The chaperone proteins heat shock protein-90 (Hsp90) and Hsp40 are necessary for the correct formation of AR?s tertiary structure. Subsequently a second co-chaperone, C-terminal Hsp interacting protein (CHIP), was characterized and found to bind HSP 70 and 90. CHIP contains E3 ligase activity which targets proteins for proteosomal ubiquitination. CHIP also binds directly to a highly conserved portion of AR which increases AR degradation. In cells where CHIP is overexpressed, AR synthesis is decreased and much of the AR produced has a defective tertiary structure. The addition of proteosomal inhibitors to the cells, does not restore AR levels to normal, indicating that AR degradation/suppression is occurring by non-proteosomal pathway(s) as well.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2011
- Accession Number
- ADA545181
Entities
People
- Courtney K. Phillips
Organizations
- Icahn School of Medicine at Mount Sinai