Bort6ezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt

Gustavo Ayala, Jun Yan, Rile Li, Yi Ding, Timothy C. Thompson, Martha P. Mims, Teresa G. Hayes, Vivian MacDonnell, R. Garret Lynch, Anna Frolov, Brian J. Miles, Thomas M. Wheeler, J. Wade Harper, Ming Jer Tsai, Michael M. Ittmann, Dov Kadmon

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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-κB. 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.

Original languageEnglish (US)
Pages (from-to)7511-7518
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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