Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.
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.
Ayala
Gustavo
G
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA. gayala@bcm.edu
Yan
Jun
J
Li
Rile
R
Ding
Yi
Y
Thompson
Timothy C
TC
Mims
Martha P
MP
Hayes
Teresa G
TG
MacDonnell
Vivian
V
Lynch
R Garret
RG
Frolov
Anna
A
Miles
Brian J
BJ
Wheeler
Thomas M
TM
Harper
J Wade
JW
Tsai
Ming-Jer
MJ
Ittmann
Michael M
MM
Kadmon
Dov
D
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
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