Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells.
Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Hui-Kuan
HK
Lin
Saleh
S
Altuwaijri
Wen-Jye
WJ
Lin
Pu-Yeh
PY
Kan
Loretta L
LL
Collins
Chawnshang
C
Chang
D021581:Active Transport, Cell Nucleus; D000728:Androgens / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D013347:Subcellular Fractions; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D000728:Androgens; D009097:Multienzyme Complexes; D011944:Receptors, Androgen; D008156:Luciferases; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex