A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers

Jianyu Cai, Xiaohong Xia, Yuning Liao, Ningning Liu, Zhiqiang Guo, Jinghong Chen, Li Yang, Huidan Long, Qianqian Yang, Xiaolan Zhang, Lu Xiao, Xuejun Wang, Hongbiao Huang, Jinbao Liu

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrateresistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines. Here, we studied the therapeutic effect of b-AP15 in PCa, and our results indicate that (i) b-AP15 decreases viability, proliferation and triggers cytotoxicity to both androgen receptor-dependent and -independent PCa cells in vitro and in vivo, associated with caspase activation, inhibition of mitochondria function, increased reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress; (ii) pan-caspase inhibitor z-VAD-FMK and ROS scavenger N-acetyl-L-cysteine (NAC) efficiently block apoptosis but not proteasome inhibition induced by exposure of b-AP15; (iii) treatment with b-AP15 in androgen-dependent prostate cancer (ADPC) cells down-regulates the expression of androgen receptor (AR), which is degraded via the ubiquitin proteasome system. Hence, the potent anti-tumor effect of b-AP15 on both androgen receptor-dependent and -independent PCa cells identifies a new promising therapeutic strategy for prostate cancer.

Original languageEnglish (US)
Pages (from-to)63232-63246
Number of pages15
JournalOncotarget
Volume8
Issue number38
DOIs
StatePublished - 2017

Keywords

  • Apoptosis
  • Deubiquitinase inhibitor
  • Prostate cancer
  • b-AP15

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Cai, J., Xia, X., Liao, Y., Liu, N., Guo, Z., Chen, J., Yang, L., Long, H., Yang, Q., Zhang, X., Xiao, L., Wang, X., Huang, H., & Liu, J. (2017). A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers. Oncotarget, 8(38), 63232-63246. https://doi.org/10.18632/oncotarget.18774