TY - JOUR
T1 - A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers
AU - Cai, Jianyu
AU - Xia, Xiaohong
AU - Liao, Yuning
AU - Liu, Ningning
AU - Guo, Zhiqiang
AU - Chen, Jinghong
AU - Yang, Li
AU - Long, Huidan
AU - Yang, Qianqian
AU - Zhang, Xiaolan
AU - Xiao, Lu
AU - Wang, Xuejun
AU - Huang, Hongbiao
AU - Liu, Jinbao
N1 - Funding Information:
The study was supported by the National Natural Science Foundation of China (81472390/ H1619, 81472762/H1609), The National Funds for developing local colleges and universities (B16056001), General Project (1201410188) from Guangzhou Education Commission, the Science and Technology Program of Guangzhou (201604020001), the Science and Technology Planning Project of Guangdong Province, China (2014A020212691) anda Research Award Fund for Outstanding Young Teachers in Guangdong Provincial Higher Education Institutions (YQ2015136) and the Project of Department of Education of Guangdong Province (2016KTSCX119). We thank Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University for flow cytometry analysis.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Deubiquitinase inhibitor
KW - Prostate cancer
KW - b-AP15
UR - http://www.scopus.com/inward/record.url?scp=85029813632&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029813632&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18774
DO - 10.18632/oncotarget.18774
M3 - Article
C2 - 28968984
AN - SCOPUS:85029813632
VL - 8
SP - 63232
EP - 63246
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 38
ER -