title: New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells.
abstract: Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten(+/-) mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.
authors.affiliation: Department of Pathology, Urology, and Radiation Oncology, the George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Chang
authors.forename: Chin-Ying
authors.initials: CY
authors.lastname: Chung
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002369:Castration; D045744:Cell Line, Tumor; D018890:Chemoprevention; D003474:Curcumin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D060588:LIM Domain Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003474:Curcumin; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D056918:Nuclear Receptor Coactivators; D051059:PTEN Phosphohydrolase; D011944:Receptors, Androgen; C471106:ASC-J9 compound; C111382:NCOA4 protein, human; C490351:TGFB1I1 protein, human; C487757:Pten protein, mouse