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Bortezomib-Mediated Inhibition of Steroid Receptor Coactivator-3 Degradation Leads to Activated Akt

Authors' Affiliations: Departments of ¹ Pathology, ² Urology, ³ Molecular and Cell Biology, and ⁴ Medicine, Baylor College of Medicine, and ⁵ Department of Pathology, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Gustavo Ayala, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. Phone: 713-798-3705; Fax: 713-798-2720; E-mail: gayala{at}bcm.edu.

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-B. 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.