title: Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells.
abstract: Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor kappaB (NF-kappaB) 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 p21(waf1) and p53. In addition, we found that PS-341 down-regulated both 5alpha-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.
authors.affiliation: Department of Internal Medicine, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. ikezoet@med.kochi-ms.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Tsuyako
authors.initials: T
authors.lastname: Saito
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Taguchi
mesh_terms: D000728:Androgens / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000378:metabolism* / Q000494:pharmacology; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D017430:Prostate-Specific Antigen / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011719:Pyrazines / Q000378:metabolism* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D000728:Androgens; D001897:Boronic Acids; D011719:Pyrazines; D011944:Receptors, Androgen; D000069286:Bortezomib; D017430:Prostate-Specific Antigen