Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth.
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.
Liu
Shicheng
S
Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057, Japan. liusc59@yahoo.co.jp
Yuan
Yiming
Y
Okumura
Yutaka
Y
Shinkai
Norihiro
N
Yamauchi
Hitoshi
H
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
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