Chaperone Function in Androgen-Independent Prostate Cancer
Abstract
The basis of this project is our finding that the Hsp90 co-chaperone, FKBP51, is upregulated at both the protein and mRNA levels in androgen independent human prostate cancer cells, LAPC-4 AI. Using biochemical approaches we found FKBP51 promotes assembly of a superchaperone complex containing ATP-bound Hsp90, p23, and FKBP51. Overexpression of FKBP51 leads to formation of maximal number of Apo-AR complexes, thereby increasing the number of AR molecules that bind hormone. FKBP51 enhances AR-dependent transcription of genes including PSA in response to both androgens and androgen-antagonists. Over-expression of FKBP51 enhances both AI and AD prostate cell growth in culture. Our working model is that FKBP51 determines androgen responsiveness in prostate cancer cells. By increasing the number of functional AR molecules that form in a low-androgen environment, over-expression of FKBP51 contributes to disease progression through androgen signaling and prostate cell proliferation. Drugs to FKBP51 may provide a complement or alternative to existing prostate cancer therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA600480
Entities
People
- Bryce Paschal
Organizations
- University of Virginia