title: Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7.
abstract: OBJECTIVE
  Failure of endocrine treatment in castration-resistant prostate cancer (CRPC) is often associated with the emergence of C-terminally truncated androgen receptor variants that function as constitutively active transcription factors (i.e., AR∆LBD). The mechanisms involved in the regulation of AR∆LBD signaling are largely unknown. Since the IGF-1 pathway was repeatedly shown to affect AR function, we studied whether an inhibition of IGF-1R could also affect AR∆LBD signaling.
  
  
  METHODS
  Regulation of androgen receptor (AR) and AR∆LBD signaling was analyzed by reporter gene assays, immunoblotting, ELISA and quantitative RT-PCR.
  
  
  RESULTS
  Inhibition of IGF-1R with the small-molecule inhibitor NVP-AEW541 reduced the transcriptional activity of the AR and its truncated counterparts Q640X and AR-V7. As shown in Q640X, the inhibition of transcriptional activity was paralleled by a decreased receptor phosphorylation.
  
  
  CONCLUSIONS
  Inhibition of IGF-1R leads to a down-regulation of AR∆LBD signaling and provides a rationale for CRPC therapies targeting growth factor receptors.
authors: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors: Friedemann
authors: F
authors: Zengerling
authors: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors: Anca
authors: A
authors: Azoitei
authors: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors: Alexander
authors: A
authors: Herweg
authors: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors: Florian
authors: F
authors: Jentzmik
authors: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany. marcus.cronauer@uni-ulm.de.
authors: Marcus V
authors: MV
authors: Cronauer
mesh_terms: D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000209:etiology* / Q000473:pathology; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D007334:Insulin-Like Growth Factor I
keywords: AR-V7; Castration-resistant prostate cancer; IGF-1 receptor; Q640X