Open AccessTargeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells
Author(s) -
Johanny Tonos De Leon,
Aki Iwai,
Clémentine Féau,
Yenni A. Garcia,
Heather A. Balsiger,
Cheryl L. Storer,
Raquel M. Suro,
Kristine M. Garza,
Sunmin Lee,
Yeong Sang Kim,
Yu Chen,
Ning Yang,
Daniel L. Riggs,
Robert J. Fletterick,
R. Kiplin Guy,
Jane B. Trepel,
Leonard Μ. Neckers,
Marc B. Cox
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1105160108
Subject(s) - androgen receptor , prostate cancer , lncap , hsp90 , cancer research , biology , receptor , androgen , heat shock protein , endocrinology , medicine , cancer , hormone , biochemistry , gene
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.