PT - JOURNAL ARTICLE AU - Tetsuo Mashima AU - Sachiko Okabe AU - Hiroyuki Seimiya TI - Pharmacological targeting of constitutively active truncated androgen receptor by nigericin and suppression of hormone-refractory prostate cancer cell growth AID - 10.1124/mol.110.064790 DP - 2010 Aug 13 TA - Molecular Pharmacology PG - mol.110.064790 4099 - http://molpharm.aspetjournals.org/content/early/2010/08/13/mol.110.064790.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/08/13/mol.110.064790.full AB - In prostate cancer, blockade of androgen receptor (AR) signaling confers a therapeutic benefit. Nevertheless, this standard therapy allows relapse of hormone-refractory prostate cancer (HRPC) with a poor prognosis. HRPC cells often express variant ARs, such as point-mutated alleles and splicing isoforms, resulting in androgen-independent cell growth and resistance to antiandrogen (e.g., flutamide). However, a pharmacological strategy to block such aberrant ARs remains to be established. Here we established a reporter system that monitors AR-mediated activation of a prostate specific antigen (PSA) promoter. Our chemical library screening revealed that the antibiotic nigericin inhibits AR-mediated activation of the PSA promoter and PSA production in prostate cancer cells. Nigericin suppressed the androgen-dependent LNCaP cell growth, even though the cells expressed a flutamide-resistant mutant AR. These effects were caused by AR suppression at the mRNA and post-translational levels. In HRPC 22Rv1 cells, which express the full-length AR and the constitutively active, truncated ARs (tARs) lacking the carboxy-terminal ligand-binding domain, siRNA-mediated knockdown of both AR isoforms efficiently suppressed the androgen-independent cell growth, whereas knockdown of the full-length AR alone had no significant effect. Importantly, nigericin was able to mimic the knockdown of both AR isoforms: it reduced the expression of the full-length and the truncated ARs, and induced G1 cell cycle arrest and apoptosis of 22Rv1 cells. These observations suggest that nigericin-like compounds that suppress AR expression at the mRNA level could be applied as new-type therapeutic agents that inhibit a broad spectrum of AR variants in HRPC.