Proteasome inhibitor PS‐341 down‐regulates prostate‐specific antigen (PSA) and induces growth arrest and apoptosis of androgen‐dependent human prostate cancer LNCaP cells

Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor KB (NF‐KB) in vitro. In addition, recent clinical studies of PS‐341 have demonstrated some objective responses in individuals with relapsed, refractory MM. However, the activity of PS‐341 against non‐hematological malignancies remains to be fully elucidated. In this study, we found that PS‐341 induced growth arrest and apoptosis of androgen‐dependent human prostate cancer LNCaP cells in conjunction with markedly up‐regulated levels of p21waf1 and p53. In addition, we found that PS‐341 down‐regulated both 5α dihydrotestosterone (DHT)‐ and interleukin‐6 (IL‐6)‐induced expression of prostate‐specific antigen (PSA) as measured by western blot analysis. PS‐341 down‐regulated basal levels of the androgen receptor (AR) in the nucleus; however, it did not affect DHT‐induced nuclear translocation of AR in these cells. Reporter assays using a series of promoters of the PSA gene showed that down‐regulation of PSA by PS‐341 was caused by inhibition of the transcriptional activity of the androgen receptor response element (ARE) in these cells. Taken together, the results indicate that PS‐341 induced growth arrest and apoptosis of LNCaP cells by blockade of the AR signaling pathway. The proteasome may be a molecular target for treatment of a variety of cancers including prostate cancer.