Maspin augments proteasome inhibitor-induced apoptosis in prostate cancer cells

✍ Scribed by Xiaohua Li; Di Chen; Shuping Yin; Yonghong Meng; Huanjie Yang; Kristin R. Landis-Piwowar; Yiwei Li; Fazlul H. Sarkar; G. Prem Veer Reddy; Q. Ping Dou; Shijie Sheng

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 338 KB
• Volume: 212
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21102

✦ Synopsis

Abstract

Proteasome inhibitors are known to induce apoptosis in a variety of cancer cells. On the other hand, maspin, a non‐inhibitory serine protease inhibitor, is shown to sensitize cancer cells to therapeutic agents that induce apoptosis. We examined the consequence of maspin expression in prostate cancer cells targeted for treatment with various proteasome inhibitors. We observed that proteasome inhibitors induced apoptosis more effectively in maspin transfected human prostate cancer DU145 cells than in control cells. Interestingly, increased apoptosis in these cells was associated with a significant induction of maspin expression. MG‐132, a proteasome inhibitor, induced endogenous and ectopic [cytomegalovirus promoter (CMV)‐driven] maspin expression, and maspin siRNA attenuated MG‐132‐induced apoptosis. Proteasome inhibitor‐induced maspin expression was inhibited by actinomycin D (Act D) and cyclohexamide (CHX), and by the inhibitors of p38MAPK, but not ERK1/2 or NF‐κB. Electrophoretic mobility‐shift assay (EMSA) and promoter‐reporter activity analyses suggested that p38MAPK activated transcription factor AP‐1 is responsible for proteasome inhibitor‐induced maspin expression. Taken together, these observations demonstrate that proteasome inhibitors induce maspin expression by activating p38MAPK pathway, and that maspin thus expressed, in turn, augments proteasome inhibitor‐induced apoptosis in prostate cancer cells. Our results suggest that gene therapy involving ectopic maspin expression may dramatically improve the efficacy of proteasome inhibitors for the treatment of prostate cancer. J. Cell. Physiol. 212: 298–306, 2007. © 2007 Wiley‐Liss, Inc.