title: Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells.
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.
authors.affiliation: Department of Urology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
authors.forename: Yue-Qing
authors.initials: YQ
authors.lastname: Tang
authors.forename: Bang-Min
authors.initials: BM
authors.lastname: Han
authors.forename: Xin-Quan
authors.initials: XQ
authors.lastname: Yao
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Fu-Jun
authors.initials: FJ
authors.lastname: Zhao
authors.forename: Sheng-Qiang
authors.initials: SQ
authors.lastname: Yu
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Sun
authors.forename: Shu-Jie
authors.initials: SJ
authors.lastname: Xia
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D013196:Dihydrotestosterone; D046988:Proteasome Endopeptidase Complex