Calpain-mediated androgen receptor breakdown in apoptotic prostate cancer cells

✍ Scribed by Huanjie Yang; Shalini Murthy; Fazlul H. Sarkar; Shijie Sheng; G. Prem-Veer Reddy; Q. Ping Dou

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 210 KB
• Volume: 217
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21565

✦ Synopsis

Abstract

Since androgen receptor (AR) plays an important role in prostate cancer development and progression, androgen‐ablation has been the frontline therapy for treatment of advanced prostate cancer even though it is rarely curative. A curative strategy should involve functional and structural elimination of AR from prostate cancer cells. We have previously reported that apoptosis induced by medicinal proteasome‐inhibitory compound celastrol is associated with a decrease in AR protein levels. However celastrol‐stimulated events contributing to this AR decrease have not been elucidated. Here, we report that a variety of chemotherapeutic agents, including proteasome inhibitors, a topoisomerase inhibitor, DNA‐damaging agents and docetaxel that cause cell death, decrease AR levels in LNCaP prostate cancer cells. This decrease in AR protein levels was not due to the suppression of AR mRNA expression in these cells. We observed that a proteolytic activity residing in cytosol of prostate cancer cells is responsible for AR breakdown and that this proteolytic activity was stimulated upon induction of apoptosis. Interestingly, proteasome inhibitor celastrol‐ and chemotherapeutic drug VP‐16‐stimulated AR breakdown was attenuated by calpain inhibitors calpastatin and N‐acetyl‐L‐leucyl‐L‐leucyl‐L‐methioninal. Furthermore, AR proteolytic activity pulled down by calmodulin‐agarose beads from celastrol‐treated PC‐3 cells showed immunoreactivity to a calpain antibody. Taken together, these results demonstrate calpain involvement in proteasome inhibitor‐induced AR breakdown, and suggest that AR degradation is intrinsic to the induction of apoptosis in prostate cancer cells. J. Cell. Physiol. 217: 569–576, 2008. © 2008 Wiley‐Liss, Inc.