Li Luo, Du Zhongbo, Gao Yingying, Tang Yu, Fan Yanru, Sun Wei, Li Ting, Liu Nanjing, Yuan Mengjuan, Fan Jiaxin, Niu Lingfang, Yan Jinxiao, Duan Limei, Wu Xiaohou, Luo Chunli
Key Laboratory of Diagnostics Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China.
Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China.
J Cell Physiol. 2019 Sep;234(9):15472-15486. doi: 10.1002/jcp.28195. Epub 2019 Jan 26.
Most prostate cancers (Pcas) develop into castration-resistant prostate cancer (CRPC) after receiving androgen deprivation therapy (ADT). The expression levels of PLCε and wnt3a are increased in Pca and regulate androgen receptor (AR) activity. However, the biological function and mechanisms of PLCε and wnt3a in CRPC remain unknown. In this study, we found that the expression levels of PLCε, wnt3a, and AR were significantly increased in CRPC tissues as well as bicalutamide-resistant-LNCaP and enzalutamide-resistant-LNCaP cells. In addition, PLCε knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and enzalutamide by inhibiting the activity of the wnt3a/β-catenin/AR signaling axis. Interestingly, the resistance of LNCaP cells docetaxel is related to PLCε but not the wnt3a/β-catenin pathway. We also found that the combination of PLCε knockdown and enzalutamide treatment synergistically suppressed cell proliferation, tumor growth, and bone metastasis using in vitro and in vivo experiments. Our study revealed that PLCε is involved in the progression of drug-resistance in CRPC and could be a new target for the treatment of CRPC.
大多数前列腺癌（Pca）在接受雄激素剥夺治疗（ADT）后会发展为去势抵抗性前列腺癌（CRPC）。Pca中PLCε和wnt3a的表达水平升高，并调节雄激素受体（AR）活性。然而，PLCε和wnt3a在CRPC中的生物学功能及机制仍不清楚。在本研究中，我们发现CRPC组织以及比卡鲁胺耐药的LNCaP细胞和恩杂鲁胺耐药的LNCaP细胞中，PLCε、wnt3a和AR的表达水平显著升高。此外，敲低PLCε通过抑制wnt3a/β-连环蛋白/AR信号轴的活性，部分恢复了耐药细胞对比卡鲁胺和恩杂鲁胺的敏感性。有趣的是，LNCaP细胞对多西他赛的耐药性与PLCε有关，而与wnt3a/β-连环蛋白途径无关。我们还通过体外和体内实验发现，敲低PLCε与恩杂鲁胺治疗联合使用可协同抑制细胞增殖、肿瘤生长和骨转移。我们的研究表明，PLCε参与了CRPC的耐药进展，可能是CRPC治疗的一个新靶点。
