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Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells
Cancer Sci | March 2004 | vol. 95 | no. 3,-0001,():
Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor κB (NF-κB) 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. (Cancer Sci 2004; 95: 271–275)
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