title: Increased resistance to trail-induced apoptosis in prostate cancer cells selected in the presence of bicalutamide.
abstract: BACKGROUND
  Following prolonged treatment with the non-steroidal anti-androgen bicalutamide (Casodex), LNCaP cells have become resistant to this drug. Previously, we found that the bicalutamide-refractory subline LNCaP-Bic acquires a growth advantage and does not respond to androgenic stimulation. In the present study, we have asked whether changes in response to the tumor-selective apoptosis inducer TNF-related apoptosis-inducing ligand (TRAIL) occur in LNCaP-Bic cells.
  
  
  METHODS
  LNCaP and LNCaP-Bic cells were incubated with increasing concentrations of TRAIL and apoptosis rate was analyzed using FACS. Expression of death receptors (DR), adaptor protein Fas-associated death domain (FADD), members of the Bcl-2 family, and caspases were investigated by Western blot.
  
  
  RESULTS
  The percentage of cells undergoing apoptosis was lower in LNCaP-Bic in comparison to LNCaP cells. There were no major differences in death receptor expression between control LNCaP and bicalutamide-selected cells. Surprisingly, treatment with TRAIL increased the levels of Bcl-2 by 50% in LNCaP-Bic cells. The ratio cleaved caspase/procaspase-8 was substantially lower in LNCaP-Bic cells.
  
  
  CONCLUSIONS
  Reduced sensitivity to TRAIL-induced apoptosis is a novel mechanism relevant to resistance to bicalutamide in prostate cancer. Inability of TRAIL to cause programmed cell death might be caused by multiple perturbations in the TRAIL-signaling pathway.
authors.affiliation: Department of Urology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Mitterberger
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.forename: Ilaria T
authors.initials: IT
authors.lastname: Cavarretta
authors.forename: Alfred
authors.initials: A
authors.lastname: Hobisch
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D053218:Receptors, Death Domain / Q000032:analysis / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014105:Tosyl Compounds; D051028:bcl-2-Associated X Protein; C053541:bicalutamide; D020169:Caspases