Yang Yanrong, Liu Taiyuan, Hu Cheng, Xia Hongyan, Liu Wei, Chen Junyu, Wu Shan, Jiang Yu, Xu Yang, Liu Wanxia, Zhao Lijing
Department of Recovery, Nursing School, Jilin University, Changchun, Jilin 130021, P.R. China.
Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
Oncol Rep. 2021 Apr;45(4). doi: 10.3892/or.2021.7976. Epub 2021 Mar 2.
To date, there is no effective therapy available for the treatment of castration‑resistant prostate cancer (CRPC), and patients generally succumb to the disease within 2 to 4 years. In the progression of CRPC, androgen receptor (AR) and its splice variants play critical roles. Hence, it is necessary to develop a drug to inhibit the expression and activity of the full‑length and splice variants of AR for the treatment of CRPC. Erastin, as the first discovered drug to induce ferroptosis, has been studied in various types of cancer. However, there are few studies focusing on the relationship between erastin and AR. In the present study, western blotting, and sulforhodamine B cell viability, glutathione, lipid peroxidation and reactive oxygen species assays were performed to verify the ferroptosis of CRPC cells; reverse transcription‑quantitative polymerase chain reaction, dual‑luciferase reporter, and lentiviral packaging and lentivirus‑infected cell assays were employed to evaluate how erastin affects AR. A mouse xenograft assay was used to determine the underlying mechanism in vivo. Erastin, as a classical inducer of ferroptosis, can suppress the transcriptional activities of both the full‑length and splice variants in AR models in vitro and in vivo. In addition, when erastin was used for CRPC treatment combined with docetaxel, the growth inhibitory efficacy of docetaxel was found to be enhanced. Thus, these findings indicated that ferroptosis inducer erastin has potential in the treatment of CRPC via targeting AR.
迄今为止，尚无有效的疗法可用于治疗去势抵抗性前列腺癌（CRPC），患者通常在2至4年内死于该疾病。在CRPC的进展过程中，雄激素受体（AR）及其剪接变体起着关键作用。因此，有必要开发一种药物来抑制AR全长和剪接变体的表达及活性，以治疗CRPC。埃拉斯汀作为首个被发现可诱导铁死亡的药物，已在多种癌症类型中进行了研究。然而，很少有研究关注埃拉斯汀与AR之间的关系。在本研究中，进行了蛋白质免疫印迹法以及磺基罗丹明B细胞活力、谷胱甘肽、脂质过氧化和活性氧检测，以验证CRPC细胞的铁死亡；采用逆转录定量聚合酶链反应、双荧光素酶报告基因检测以及慢病毒包装和慢病毒感染细胞检测，来评估埃拉斯汀如何影响AR。使用小鼠异种移植试验来确定体内的潜在机制。埃拉斯汀作为一种经典的铁死亡诱导剂，在体外和体内的AR模型中均可抑制全长和剪接变体的转录活性。此外，当埃拉斯汀与多西他赛联合用于CRPC治疗时，发现多西他赛的生长抑制效果增强。因此，这些研究结果表明，铁死亡诱导剂埃拉斯汀通过靶向AR在CRPC治疗中具有潜力。
