title: Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth.
abstract: The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser(81) and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.
authors.affiliation: Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057, Japan. liusc59@yahoo.co.jp
authors.forename: Shicheng
authors.initials: S
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okumura
authors.forename: Norihiro
authors.initials: N
authors.lastname: Shinkai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamauchi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D059004:Topoisomerase I Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin