title: Mifepristone inhibits GRβ coupled prostate cancer cell proliferation.
abstract: OBJECTIVE
  The GR gene produces GRα and GRβ isoforms by alternative splicing of a C-terminal exon. GRα binds glucocorticoids, modulates transcription in a glucocorticoid dependent manner and has a growth inhibitory role in prostate cells. Due to this role glucocorticoids are often used to treat androgen independent prostate cancer. In contrast, GRβ has intrinsic transcriptional activity and binds mifepristone (RU486) but not glucocorticoids to control gene expression. To our knowledge the role of GRβ in prostate cell proliferation is unknown.
  
  
  METHODS
  We determined GRβ levels in various prostate cancer cell lines by reverse transcriptase-polymerase chain reaction and Western blot. The effect of GRβ on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined after siRNA mediated knockdown and over expression of GRβ.
  
  
  RESULTS
  GRβ mRNA and protein were up-regulated in LNCaP cells that over expressed the androgen receptor co-factor ARA70β. Treatment of LNCaP-ARA70β with mifepristone or siRNA targeting GRβ inhibited proliferation compared to that of parental LNCaP cells. The immortal but nontumorigenic RC165 prostate cell line and the tumorigenic DU145 prostate cell line with endogenous GRβ also showed partial growth reduction upon GRβ depletion but to a lesser extent than LNCaP-ARA70β cells. The growth stimulatory effect of ARA70β on LNCaP cells was partly GRβ dependent, as was the proliferation of RC165 cells and to a lesser extent of DU145 cells.
  
  
  CONCLUSIONS
  Results suggest that patients with a primary tumor that expresses GRβ and ARA70β may benefit from mifepristone.
authors: Department of Pathology, New York University School of Medicine, New York, New York 10010, USA.
authors: Martin
authors: M
authors: Ligr
authors: Yirong
authors: Y
authors: Li
authors: Susan K
authors: SK
authors: Logan
authors: Samir
authors: S
authors: Taneja
authors: Jonathan
authors: J
authors: Melamed
authors: Hebert
authors: H
authors: Lepor
authors: Michael J
authors: MJ
authors: Garabedian
authors: Peng
authors: P
authors: Lee
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; C121943:glucocorticoid receptor beta; D015735:Mifepristone