Inhibition of heat shock protein 90 (Hsp90) and degradation of client proteins associated with oncogenesis using analogs of Novobiocin
Abstract
Prostate cancer remains a lethal disease with over 30,000 men dying per year. Thus, there is a critical need to develop novel therapies that translate to improved clinical outcomes. The objective of these studies is to design C‐terminal inhibitors of the molecular chaperone hsp90 resulting in client protein degradation and inhibition of multiple signaling pathways causing cancer cell death of in vitro and in vivo. C‐terminal inhibitors of hsp90 were tested in a dose response manner using the androgen independent PC‐3 prostate cancer cell line by Western blot analysis and examined degradation of client proteins (AKT, HER2, and BCL‐2). Additionally, one inhibitor, KU32, was used in an in vivo orthotopic murine tumor model and examined for reduction of prostate serum antigen (PSA) and degradation of client protein in treated and untreated animals. Prostate cancer cells treated with these inhibitors demonstrated the hallmarks of hsp90 inhibition, specifically, the increased expression of hsp90 and decreased expression of client proteins in a dose dependent fashion. The in vivo studies are currently ongoing. These data suggest that C‐terminal inhibitors may debilitate cancer cell function and slow tumor cell proliferation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2008
- Source ID
- 10.1096/fasebj.22.1_supplement.1136.20
Entities
People
- Brian Blagg
- George Vielhauer
- Jeff Holzbeierlein
- Michelle Higgins
- Scott J Weir
Organizations
- Kansas State University
- National Cancer Institute
- United States Department of Defense
- University of Kansas