Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells.
- Author:
Yue-Qing TANG
1
;
Bang-Min HAN
;
Xin-Quan YAO
;
Yan HONG
;
Yan WANG
;
Fu-Jun ZHAO
;
Sheng-Qiang YU
;
Xiao-Wen SUN
;
Shu-Jie XIA
Author Information
- Publication Type:Journal Article
- MeSH: Cell Line, Tumor; Cell Proliferation; drug effects; Cell Survival; drug effects; Dihydrotestosterone; pharmacology; Dose-Response Relationship, Drug; Humans; Male; Prostatic Neoplasms; drug therapy; metabolism; pathology; Proteasome Endopeptidase Complex; metabolism; Receptors, Androgen; metabolism; Recombinant Fusion Proteins; pharmacology; therapeutic use; Signal Transduction; drug effects; Ubiquitin; metabolism
- From: Asian Journal of Andrology 2009;11(1):119-126
- CountryChina
- Language:English
- Abstract: Post-translational degradation of protein plays an important role in cell life. We employed chimeric molecules (dihydrotestosterone-based proteolysis-targeting chimeric molecule [DHT-PROTAC]) to facilitate androgen receptor (AR) degradation via the ubiquitin-proteasome pathway (UPP) and to investigate the role of AR in cell proliferation and viability in androgen-sensitive prostate cancer cells. Western blot analysis and immunohistochemistry were applied to analyse AR levels in LNCaP cells after DHT-PROTAC treatment. Cell counting and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay were used to evaluate cell proliferation and viability after AR elimination in both LNCaP and PC-3 cells. AR was tagged for elimination via the UPP by DHT-PROTAC, and this could be blocked by proteasome inhibitors. Degradation of AR depended on DHT-PROTAC concentration, and either DHT or an ALAPYIP-(arg)(8) peptide could compete with DHT-PROTAC. Inhibition of cell proliferation and decreased viability were observed in LNCaP cells, but not in PC-3 or 786-O cells after DHT-PROTAC treatment. These data indicate that AR elimination is facilitated via the UPP by DHT-PROTAC, and that the growth of LNCaP cells is repressed after AR degradation.
