A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers
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Jianyu Cai1,*, Xiaohong Xia1,*, Yuning Liao1,*, Ningning Liu1,2, Zhiqiang Guo1, Jinghong Chen1, Li Yang1, Huidan Long1, Qianqian Yang1, Xiaolan Zhang1, Lu Xiao1, Xuejun Wang1,3, Hongbiao Huang1 and Jinbao Liu1
1Protein Modification and Degradation Lab, SKLRD, School of Basic Medical Sciences, The Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong 511436, China
2Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
3Division 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
Hongbiao Huang, email: [email protected]
Jinbao Liu, email: [email protected]
Keywords: b-AP15, deubiquitinase inhibitor, prostate cancer, apoptosis
Received: February 18, 2017 Accepted: May 22, 2017 Published: June 28, 2017
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.
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