@article {Mashima846, author = {Tetsuo Mashima and Sachiko Okabe and Hiroyuki Seimiya}, title = {Pharmacological Targeting of Constitutively Active Truncated Androgen Receptor by Nigericin and Suppression of Hormone-Refractory Prostate Cancer Cell Growth}, volume = {78}, number = {5}, pages = {846--854}, year = {2010}, doi = {10.1124/mol.110.064790}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 lacking the carboxyl-terminal ligand-binding domain, small interfering RNA-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. It is noteworthy that nigericin was able to mimic the knockdown of both AR isoforms: it reduced the expression of the full-length and the truncated ARs, and it 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/78/5/846}, eprint = {https://molpharm.aspetjournals.org/content/78/5/846.full.pdf}, journal = {Molecular Pharmacology} }