title: Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer.
abstract: BACKGROUND
  Dexamethasone, a synthetic glucocorticoid, has clinical benefit in patients with hormone-refractory prostate cancer (HRPC), but the mechanisms responsible for its effects are unknown. The nuclear factor-kappaB (NF-kappaB)-dependent cytokine interleukin (IL) 6 (IL-6) is thought to stimulate growth of HRPC. Because dexamethasone interferes with NF-kappaB activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-kappaB-IL-6 pathway.
  
  
  METHODS
  Three human prostate cancer cell lines (DU145, PC-3, and LNCaP) were assessed for GR expression and responsiveness to dexamethasone. Levels of GR, NF-kappaB, and the cytoplasmic NF-kappB inhibitor IkappaBalpha were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF-kappaB was analyzed by immunofluorescence. The effects of dexamethasone (thrice weekly injections of 1 microg/mouse) on DU145 xenografts in nude and severe combined immunodeficient (SCID) mice were evaluated. GR expression in human prostate cancers was assessed by immunohistochemistry. All statistical tests were two-sided.
  
  
  RESULTS
  Dexamethasone dose dependently decreased GR levels and inhibited the growth of DU145 and PC-3 but not LNCaP cells (DU145 cells, P< .001; PC-3 cells, P = .009). Dexamethasone increased IkappaBalpha protein levels and the cytosolic accumulation of NF-kappaB in DU145 cells and decreased secreted IL-6 levels to 37 pg/mL (95% confidence interval [CI] = 33 pg/mL to 41 pg/mL), compared with 164 pg/mL (95% CI = 162 pg/mL to 166 pg/mL) secreted by ethanol-treated control cells. Dexamethasone inhibited the growth of DU145 xenografts in nude (P = .006) and SCID (P = .026) mice without affecting GR levels. Eight of 16 human prostate cancers expressed GR at high levels (>or=30% GR-positive cells).
  
  
  CONCLUSIONS
  Dexamethasone inhibited the growth of GR-positive cancers, possibly through the disruption of the NF-kappaB-IL-6 pathway.
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Suita-City, Japan. kazu@uro.med.osaka-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Nishimura
authors.forename: N
authors.initials: N
authors.lastname: Nonomura
authors.forename: E
authors.initials: E
authors.lastname: Satoh
authors.forename: Y
authors.initials: Y
authors.lastname: Harada
authors.forename: M
authors.initials: M
authors.lastname: Nakayama
authors.forename: T
authors.initials: T
authors.lastname: Tokizane
authors.forename: T
authors.initials: T
authors.lastname: Fukui
authors.forename: Y
authors.initials: Y
authors.lastname: Ono
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Shin
authors.forename: Y
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: H
authors.initials: H
authors.lastname: Takayama
authors.forename: K
authors.initials: K
authors.lastname: Aozasa
authors.forename: A
authors.initials: A
authors.lastname: Okuyama
mesh_terms: D000728:Androgens / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011965:Receptors, Glucocorticoid; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone