The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way

Prostate. 2013 Feb 15;73(3):267-77. doi: 10.1002/pros.22566. Epub 2012 Jul 20.

Abstract

Background: The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known.

Methods: We analyzed potential signaling pathways associated with AR-V7 constitutive activation in PTEN (-) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway.

Results: In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation.

Conclusions: Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration-resistant PC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Castration
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Disease Progression
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism*
  • Genetic Variation / genetics
  • Humans
  • Male
  • Morpholines / pharmacology
  • PTEN Phosphohydrolase / metabolism*
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Signal Transduction / physiology*
  • Transcription, Genetic / drug effects
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Morpholines
  • Protein Isoforms
  • Receptors, Androgen
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Wortmannin