Chen Haojie, Luo Jia, Chen Shaojun, Shi Bowen, Zheng Xiaocui, Ji Haiying, Zhang Xiaoqian, Yin Yujia, Du Kun, Ding Jie, Yu Yongjiang
Department of Urology, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200092, P. R. China.
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Cell Death Discov. 2022 May 3;8(1):241. doi: 10.1038/s41420-022-00951-4.
Drug resistance is responsible for castration-resistant prostate cancer (CRPC)-associated mortality. While ATP binding cassette subfamily C member 5 (ABCC5) has been reported to regulate multiple drug resistance, its drug-efflux function may not be the main reason underlying resistance to enzalutamide, an androgen receptor inhibitor. Here, we aimed to determine whether the non-drug efflux function of ABCC5 affects enzalutamide resistance. The ABCC5 expression data in patients with prostate cancer (PCa) were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus, and their correlation with disease prognosis was analyzed. Immunohistochemical staining was performed on a cohort of 80 patient samples. Proliferation of enzalutamide-resistant 22RV1 and C4-2B cells was investigated using CCK-8, EdU, and colony formation assays. The effect of ABCC5 silencing on enzalutamide resensitization was evaluated in vitro and in vivo. Functional assays indicated that ABCC5 depletion resensitized enzalutamide-resistant cells to inhibit cell growth and impeded xenograft tumor proliferation. Mechanistically, luciferase and ChIP assays confirmed that P65 regulated AR expression and activity by binding to its promoter, while ABCC5-mediated resistance effected by AR-V7 (one of the widely studied AR splicing variants that meditate AR antagonist resistance) upregulation could be reversed by P65 knockdown. Furthermore, activation of the NF-κB pathway reversed the effects of ABCC5 knockdown by extra AR-V7 expression. Thus, ABCC5 might be a novel target for enzalutamide-resistant CRPC treatment.
耐药性是去势抵抗性前列腺癌（CRPC）相关死亡率的原因。虽然据报道ATP结合盒亚家族C成员5（ABCC5）可调节多重耐药性，但其药物外排功能可能不是对雄激素受体抑制剂恩杂鲁胺耐药的主要原因。在此，我们旨在确定ABCC5的非药物外排功能是否影响恩杂鲁胺耐药性。从癌症基因组图谱和基因表达综合数据库中检索前列腺癌（PCa）患者的ABCC5表达数据，并分析其与疾病预后的相关性。对80例患者样本进行免疫组织化学染色。使用CCK-8、EdU和集落形成试验研究恩杂鲁胺耐药的22RV1和C4-2B细胞的增殖。在体外和体内评估ABCC5沉默对恩杂鲁胺再敏化的影响。功能试验表明，ABCC5缺失使恩杂鲁胺耐药细胞对抑制细胞生长重新敏感，并阻碍异种移植肿瘤增殖。从机制上讲，荧光素酶和染色质免疫沉淀试验证实，P65通过结合其启动子调节AR表达和活性，而ABCC5介导的由AR-V7（介导AR拮抗剂耐药的广泛研究的AR剪接变体之一）上调引起的耐药可通过敲低P65来逆转。此外，NF-κB通路的激活通过额外的AR-V7表达逆转了ABCC5敲低的作用。因此，ABCC5可能是恩杂鲁胺耐药CRPC治疗的新靶点。
