title: Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARΔLBD-signalling in human prostate cancer cells.
abstract: BACKGROUND
  Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens.
  
  
  METHODS
  In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay.
  
  
  RESULTS
  The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo.
  
  
  CONCLUSIONS
  RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Streicher
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Luedeke
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Anca
authors.initials: A
authors.lastname: Azoitei
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Zengerling
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Herweg
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Schrader
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Schrader
authors.affiliation: Department of Urology, Ulm University, Ulm, Germany.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Cronauer
mesh_terms: D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D011944:Receptors, Androgen; D013267:Stilbenes