Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt

Clin Cancer Res. 2008 Nov 15;14(22):7511-8. doi: 10.1158/1078-0432.CCR-08-0839.


Purpose: 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.

Experimental design: 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.

Conclusion: These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Flow Cytometry
  • Histone Acetyltransferases / drug effects*
  • Histone Acetyltransferases / metabolism
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • NF-kappa B / drug effects
  • Neoadjuvant Therapy
  • Nuclear Receptor Coactivator 3
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / analogs & derivatives
  • Prostate-Specific Antigen / blood
  • Prostate-Specific Antigen / drug effects
  • Prostatectomy
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / surgery
  • Proto-Oncogene Proteins c-akt / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazines / therapeutic use*
  • RNA Interference
  • Trans-Activators / drug effects*
  • Trans-Activators / metabolism


  • Antineoplastic Agents
  • Boronic Acids
  • NF-kappa B
  • Pyrazines
  • Trans-Activators
  • Phosphorylcholine
  • perifosine
  • Bortezomib
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • Proto-Oncogene Proteins c-akt
  • Prostate-Specific Antigen