Modulation of the tumor cell death pathway by androgen receptor in response to cytotoxic stimuli

✍ Scribed by Michael Frezza; Huanjie Yang; Q. Ping Dou

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 821 KB
• Volume: 226
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.22758

✦ Synopsis

Abstract

Despite an initial response from androgen deprivation therapy, most prostate cancer patients relapse to a hormone‐refractory state where tumors still remain dependent on androgen receptor (AR) function. We have previously shown that AR breakdown correlates with the induction of cancer cell apoptosis by proteasome inhibition. However, the involvement of AR in modulating the cell death pathway has remained elusive. To investigate this, we used an experimental model consisting of parental PC‐3 prostate cancer cells that lack AR expression and PC‐3 cells stably overexpressing wild type AR gene. Here, we report that both chemotherapeutic drugs (cisplatin) and proteasome inhibitors induced caspase‐3‐associated cell death in parental PC‐3 cells whereas non‐caspase‐3 associated cell death in PC3‐AR cells. The involvement of AR in modulating tumor cell death was further confirmed in PC‐3 cells transiently expressing AR. Consistently, treatment with the clinically used proteasome inhibitor Bortezomib (Velcade/PS‐341) of (AR+) LNCaP prostate cancer cells caused AR cleavage and cell death with low levels of caspase activation. However, co‐treatment with Bortezomib and the AR antagonist Bicalutamide (Casodex) caused significant decrease in AR expression associated with an increase in caspase‐3 activity in both LNCaP and PC3‐AR cells. Thus our results provide compelling evidence for involvement of AR in deciding types of tumor cell death upon cytotoxic stimuli, and specifically, blockade of AR activities could change necrosis to apoptosis in tumor cells. Our findings may help guide clinicians based on AR status in the design of favorable treatment strategies for prostate cancer patients. J. Cell. Physiol. 226: 2731–2739, 2011. © 2011 Wiley‐Liss, Inc.