title: PC3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor.
abstract: BACKGROUND
  Androgen receptor (AR) functions in normal prostate epithelium as a tumor suppressor to inhibit continuous proliferation of these cells. Such tumor suppressor function of AR is lost in androgen depletion independent (ADI) prostate cancers. In type-I ADI cancers AR is not expressed, while in type-II ADI cancers AR is recaptured as an oncogene. The PC3 and DU145 human prostate cancer cell lines are representative of the earlier type-I ADI prostate cancers. While these cells do not express AR, it is unclear whether they retained the coactivators necessary for AR-dependent tumor suppression. To answer this question the response to AR protein expression by PC3 and DU145 cells was evaluated.
  
  
  METHODS
  To do this, a lentiviral AR (Lenti-AR) expression system was engineered to encode an AR transcript which includes appropriate 5' and 3' untranslated regions (UTRs) containing all previously identified post-transcriptional regulatory sequences. AR expression and transcriptional activity were evaluated in Lenti-AR transduced cells by Western blot and luciferase assay, respectively. Cell growth in culture and in mouse xenografts was evaluated in correlation to expression changes in p21, p27, and p45(SKP2) proteins.
  
  
  RESULTS
  Lenti-AR transduced PC3 and DU145 lines expressed transcriptionally functional AR protein at appropriate physiological levels. Expression and engagement of AR protein in PC3-Lenti-AR cells resulted in transactivation of p21 and subsequent growth inhibition of these cells in culture and in mouse xenografts. Such inhibition was due to induced G1 arrest of these cells as documented by expression changes in p27 and p45(SKP2) proteins. Such growth inhibition was not observed in DU145-Lenti-AR cells.
  
  
  CONCLUSIONS
  These results document that PC3, but not DU145 cells retain the coregulators needed for AR tumor suppressor ability.
authors.affiliation: Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.forename: Lizamma
authors.initials: L
authors.lastname: Antony
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.forename: Robyn
authors.initials: R
authors.lastname: Becker
authors.forename: Linzhao
authors.initials: L
authors.lastname: Cheng
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D011944:Receptors, Androgen; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; C413374:p27 antigen