title: Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells.
abstract: BACKGROUND
  Recently we have reported membrane androgen receptors-induced apoptotic regression of prostate cancer cells regulated by Rho/ROCK/actin signaling. In the present study we explored the specificity of these receptors and we analyzed downstream effectors controlling survival and apoptosis in hormone refractory DU145-prostate cancer cells stimulated with membrane androgen receptor-selective agonists.
  
  
  RESULTS
  Using membrane impermeable conjugates of serum albumin covalently linked to testosterone, we show here down-regulation of the activity of pro-survival gene products, namely PI-3K/Akt and NF-kappaB, in DU145 cells. Testosterone-albumin conjugates further induced FasL expression. A FasL blocking peptide abrogated membrane androgen receptors-dependent apoptosis. In addition, testosterone-albumin conjugates increased caspase-3 and Bad protein activity. The actin cytoskeleton drug cytochalasin B and the ROCK inhibitor Y-27632 inhibited FasL induction and caspase-3 activation, indicating that the newly identified Rho/Rock/actin signaling may regulate the downstream pro-apoptotic effectors in DU145 cells. Finally, other steroids or steroid-albumin conjugates did not interfere with these receptors indicating testosterone specificity.
  
  
  CONCLUSIONS
  Collectively, our results provide novel mechanistic insights pointing to specific pro-apoptotic molecules controlling membrane androgen receptors-induced apoptotic regression of prostate cancer cells and corroborate previously published observations on the potential use of membrane androgen receptor-agonists as novel anti-tumor agents in prostate cancer.
authors.affiliation: Department of Biochemistry, University of Crete Medical School, Heraklion, Greece. npap@imbb.forth.gr
authors.forename: Natalia
authors.initials: N
authors.lastname: Papadopoulou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Vasileia
authors.initials: V
authors.lastname: Anagnostopoulou
authors.forename: Georgios
authors.initials: G
authors.lastname: Konstantinidis
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Achilleas
authors.initials: A
authors.lastname: Gravanis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Alevizopoulos
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
mesh_terms: D000728:Androgens; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000737:chemistry / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; C494819:BAD protein, human; D053222:Fas Ligand Protein; D016328:NF-kappa B; D012709:Serum Albumin; D051025:bcl-Associated Death Protein; D013739:Testosterone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3