Cai Jianyu, Xia Xiaohong, Liao Yuning, Liu Ningning, Guo Zhiqiang, Chen Jinghong, Yang Li, Long Huidan, Yang Qianqian, Zhang Xiaolan, Xiao Lu, Wang Xuejun, Huang Hongbiao, Liu Jinbao
Protein Modification and Degradation Lab, SKLRD, School of Basic Medical Sciences, The Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong 511436, China.
Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
Oncotarget. 2017 Jun 28;8(38):63232-63246. doi: 10.18632/oncotarget.18774. eCollection 2017 Sep 8.
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 and , 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 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.
前列腺癌（PCa）仍是男性癌症相关死亡的主要原因。特别是，一部分患者最终会进展为转移性去势抵抗性前列腺癌（CRPC），而这种癌症目前无法治愈。与19S蛋白酶体调节颗粒相关的去泛素化酶（DUBs）在众多癌症中日益成为重要的治疗靶点。最近，一种新型小分子b-AP15被鉴定为19S蛋白酶体的USP14/UCHL5（DUBs）抑制剂，可导致几种人类癌细胞系的细胞生长抑制和凋亡。在此，我们研究了b-AP15在PCa中的治疗效果，我们的结果表明：（i）b-AP15降低雄激素受体依赖性和非依赖性PCa细胞的活力、增殖并引发细胞毒性，这与半胱天冬酶激活、线粒体功能抑制、活性氧（ROS）生成增加和内质网（ER）应激有关；（ii）泛半胱天冬酶抑制剂z-VAD-FMK和ROS清除剂N-乙酰-L-半胱氨酸（NAC）可有效阻断b-AP15诱导的凋亡，但不能阻断蛋白酶体抑制；（iii）用b-AP15处理雄激素依赖性前列腺癌（ADPC）细胞可下调雄激素受体（AR）的表达，AR通过泛素蛋白酶体系统被降解。因此，b-AP15对雄激素受体依赖性和非依赖性PCa细胞均具有强大的抗肿瘤作用，为前列腺癌确定了一种新的有前景的治疗策略。
