Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

Johanny Tonos De Leon, Aki Iwai, Clementine Feau, Yenni Garcia, Heather A. Balsiger, Cheryl L. Storer, Raquel M. Suro, Kristine M. Garza, Sunmin Lee, Yeong Sang Kim, Yu Chen, Yang Min Ning, Daniel L. Riggs, Robert J. Fletterick, R. Kiplin Guy, Jane B. Trepel, Leonard M. Neckers, Marc B. Cox

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)11878-11883
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number29
DOIs
StatePublished - Jul 19 2011

Keywords

  • FKBP4
  • Immunophilin
  • Steroid hormone receptor

ASJC Scopus subject areas

  • General

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