Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy
Article first published online: 25 JAN 2002
Copyright © 2002 Wiley-Liss, Inc.
Volume 50, Issue 3, pages 179–188, 15 February 2002
How to Cite
July, L. V., Akbari, M., Zellweger, T., Jones, E. C., Goldenberg, S. L. and Gleave, M. E. (2002), Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate, 50: 179–188. doi: 10.1002/pros.10047
- Issue published online: 25 JAN 2002
- Article first published online: 25 JAN 2002
- Manuscript Accepted: 5 NOV 2001
- Manuscript Received: 5 APR 2001
- National Cancer Institute of Canada. Grant Number: 009002
- Swiss National Science Foundation, Krebsliga Basel, Lichtenstein-Stiftung
- Freiwillige Akademische Gesellschaft of the University of Basel, Switzerland (to Tobias Zellweger)
- prostate cancer;
- androgen withdrawal;
Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients.
MATERIALS AND METHODS
Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2–8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients.
Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P ≪ 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P ≪ 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal.
Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer. Prostate 50: 179–188, 2002. © 2002 Wiley-Liss, Inc.