Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells

Am J Pathol. 2006 Aug;169(2):682-96. doi: 10.2353/ajpath.2006.051047.


The majority of prostate cancers (PCa) that relapse after androgen deprivation therapy (androgen-independent PCa) continue to express androgen receptor (AR). To study the functional importance of AR in these tumors, we derived androgen-independent CWR22 PCa xenografts in castrated mice and generated a cell line from one of these xenografts (CWR22R3). Similarly to androgen-independent PCa in patients, the relapsed xenografts and cell line expressed AR and were resistant to treatment with bicalutamide. However, expression of the AR-regulated PSA gene in the CWR22R3 cell line was markedly decreased compared to the relapsed xenografts in vivo. Transfections with androgen-regulated reporter genes further indicated that the cells lacked androgen-independent AR transcriptional activity and were not hypersensitive to low androgen concentrations despite constitutive activation of the Erk/MAP kinases. Nonetheless, AR remained essential for androgen-independent growth because retroviral shRNA-mediated AR down-regulation resulted in marked long-term growth suppression. This was associated with increased levels of p27(kip1) and hypophosphorylation of retinoblastoma protein but not with decreases in D-type cyclin levels or MAP kinase activation. These results reveal a potentially critical function of AR in androgen-independent PCa that is distinct from its previously described transcriptional or nontranscriptional functions.

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

  • Androgens / metabolism*
  • Anilides
  • Animals
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • G1 Phase*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Neoplasm Transplantation
  • Nitriles
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prostate-Specific Antigen / genetics
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Tosyl Compounds
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Androgens
  • Anilides
  • Nitriles
  • RNA, Messenger
  • Receptors, Androgen
  • Tosyl Compounds
  • Transcription Factors
  • bicalutamide
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Prostate-Specific Antigen