The Role of the Co-Chaperone, CHIP, in Androgen-Independent Prostate Cancer
Addendum to final rept. 30 Jan 2006-29 Jan 2012
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK
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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. Within 3-4 years, the vast majority of patients develop androgen independent prostate cancer AIPC. Though several new treatments have recently been approved, once a patient develops AIPC, options are less effective, with first line chemotherapy providing only 13-15 month survival.1 The shift from androgen sensitive prostate cancer ASPC to AIPC is a seminal event in disease progression and thus it has been extensively studied. At the center of much of this research is the androgen receptor since many believe that the overexpression, mutation andor constitutive activation of this receptor play a critical role in the progression from ASPC to AIPC. 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, Cterminal 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 and can also directly bind to a highly conserved portion of AR which increases degradation. In cells where CHIP is overexpressed, AR synthesis is decreased and much of the AR produced has a defective tertiary structure which prevents degradation. The addition of proteosomal inhibitors to the cells, does not restore AR levels to normal, indicating that AR degradationsuppression is occurring by non-proteosomal pathways as well. The role of this study is to better characterize the interaction of CHIP and the androgen receptor and assess its role in disease progression.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research