New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells

Kuo Pao Lai, Chiung Kuei Huang, Yu Jia Chang, Chin Ying Chung, Shinichi Yamashita, Lei Li, Soo Ok Lee, Shuyuan Yeh, Chawnshang Chang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)460-473
Number of pages14
JournalAmerican Journal of Pathology
Volume182
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

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Castration
Androgen Receptors
Prostate
Prostatic Neoplasms
Androgens
Therapeutics
Nude Mice
Proteasome Endopeptidase Complex
Growth

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells. / Lai, Kuo Pao; Huang, Chiung Kuei; Chang, Yu Jia; Chung, Chin Ying; Yamashita, Shinichi; Li, Lei; Lee, Soo Ok; Yeh, Shuyuan; Chang, Chawnshang.

In: American Journal of Pathology, Vol. 182, No. 2, 02.2013, p. 460-473.

Research output: Contribution to journalArticle

Lai, Kuo Pao ; Huang, Chiung Kuei ; Chang, Yu Jia ; Chung, Chin Ying ; Yamashita, Shinichi ; Li, Lei ; Lee, Soo Ok ; Yeh, Shuyuan ; Chang, Chawnshang. / New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells. In: American Journal of Pathology. 2013 ; Vol. 182, No. 2. pp. 460-473.
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