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

// Jianyu Cai 1, * , Xiaohong Xia 1, * , Yuning Liao 1, * , Ningning Liu 1, 2 , Zhiqiang Guo 1 , Jinghong Chen 1 , Li Yang 1 , Huidan Long 1 , Qianqian Yang 1 , Xiaolan Zhang 1 , Lu Xiao 1 , Xuejun Wang 1, 3 , Hongbiao Huang 1 and Jinbao Liu 1 1 Protein Modification and Degradation Lab, SKLRD, School of Basic Medical Sciences, The Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong 511436, China 2 Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China 3 Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, South Dakota 57069, USA * Cai J, Xia X and Liao Y contributed equally to this work Correspondence to: Hongbiao Huang, email: hhb800616@126.com Jinbao Liu, email: jliu@gzhmu.edu.cn Keywords: b-AP15, deubiquitinase inhibitor, prostate cancer, apoptosis Received: February 18, 2017 Accepted: May 22, 2017 Published: June 28, 2017 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 castrate-resistant 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.