Cui Feilun, Ning Songyi, Xu Zhipeng, Hu Jianpeng
Department of Urology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
Transl Androl Urol. 2022 Apr;11(4):519-527. doi: 10.21037/tau-22-214.
Androgen plays a critical role in the development and growth of prostate cancer (PCa) by binding to the androgen receptor, a steroid receptor for testosterone and dihydrotestosterone (DHT). Androgen deprivation therapy, a clinical endocrine therapy, has resulted in increases in the occurrence of castration-resistant prostate cancer (CRPC); however, the mechanisms of CRPC have not yet fully been determined. We previously showed that spindle pole body component 25 (SPC25), a component of the NDC80 complex that is critical in kinetochore formation and chromosome segregation during the cell cycle, plays a critical role in PCa tumorigenesis and cancer stemness. However, it is not yet known whether SPC25 plays a role in CRPC; thus, we sought to address this question in the current study.
SPC25 levels were detected in androgen-insensitive PCa cells using the public database and bioinformatics tools. In vitro, SPC25 levels were determined in androgen-sensitive and androgen-insensitive PCa cells treated with or without DHT. The growth of the PCa cells was assessed by the Cell Counting Kit-8 assay. The invasiveness and migratory potential of the PCa cells were assessed by the transwell cell invasive assay and migratory assay, respectively. Gain-of-function and loss-of-function experiments examined the transfection of androgen-sensitive and androgen-insensitive PCa cells by plasmids carrying small-interfering ribonucleic acids for SPC25 or SPC25, respectively.
SPC25 levels were significantly reduced in the androgen-insensitive PCa cells treated with DHT in the Public database. In vitro, PCa cell growth, invasion, and metastasis was reduced in androgen-insensitive PCa cells but increased in androgen-sensitive PCa cells treated with DHT, partially through DHT-regulated expression of SPC25 at transcriptional but not at translational levels.
Androgen treatment reduces CRPC growth, invasion, and metastasis partially through its regulation of SPC25. SPC25 represents a promising target in the treatment of CRPC.
雄激素通过与雄激素受体结合，在前列腺癌（PCa）的发生和发展中起关键作用，雄激素受体是睾酮和双氢睾酮（DHT）的类固醇受体。雄激素剥夺疗法作为一种临床内分泌疗法，已导致去势抵抗性前列腺癌（CRPC）的发生率增加；然而，CRPC的发病机制尚未完全明确。我们之前的研究表明，纺锤体极体成分25（SPC25）是NDC80复合体的一个组成部分，在细胞周期中的动粒形成和染色体分离过程中起关键作用，在PCa肿瘤发生和癌症干性中也起关键作用。然而，尚不清楚SPC25是否在CRPC中发挥作用；因此，我们试图在本研究中解决这个问题。
使用公共数据库和生物信息学工具检测雄激素不敏感PCa细胞中的SPC25水平。在体外，测定用或不用DHT处理的雄激素敏感和雄激素不敏感PCa细胞中的SPC25水平。通过细胞计数试剂盒-8法评估PCa细胞的生长情况。分别通过Transwell细胞侵袭试验和迁移试验评估PCa细胞的侵袭性和迁移潜力。功能获得和功能缺失实验分别检测携带针对SPC25的小干扰核糖核酸的质粒或SPC25对雄激素敏感和雄激素不敏感PCa细胞的转染情况。
在公共数据库中，用DHT处理的雄激素不敏感PCa细胞中SPC25水平显著降低。在体外，雄激素不敏感PCa细胞中PCa细胞的生长、侵袭和转移减少，但在用DHT处理的雄激素敏感PCa细胞中增加，部分是通过DHT在转录水平而非翻译水平调节SPC25的表达。
雄激素治疗通过对SPC25的调节部分降低了CRPC的生长、侵袭和转移。SPC25是CRPC治疗中一个有前景的靶点。
