title: Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.
abstract: OBJECTIVE
  To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets.
  
  
  METHODS
  Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity.
  
  
  RESULTS
  Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-kappaB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro.
  
  
  CONCLUSIONS
  These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA. gayala@bcm.edu
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Rile
authors.initials: R
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.forename: Martha P
authors.initials: MP
authors.lastname: Mims
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Hayes
authors.forename: Vivian
authors.initials: V
authors.lastname: MacDonnell
authors.forename: R Garret
authors.initials: RG
authors.lastname: Lynch
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Miles
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Dov
authors.initials: D
authors.lastname: Kadmon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D051548:Histone Acetyltransferases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000187:drug effects; D020360:Neoadjuvant Therapy; D056921:Nuclear Receptor Coactivator 3; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use*; D034622:RNA Interference; D015534:Trans-Activators / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D015534:Trans-Activators; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen