Han Chenglin, Yang Bin, Deng Yuxuan, Hu Peng, Hu Bintao, Liu Xiaming, Wang Tao, Li Chengbao, Liu Jihong, Yuan Huixing
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
Chin Med. 2025 Mar 14;20(1):35. doi: 10.1186/s13020-025-01086-1.
Castration-resistant prostate cancer (CRPC) has been a major cause of tumor-associated death among men worldwide. The discovery of novel therapeutic medicines for CRPC remains imperative. Atractylenolide I (ATR-I), a prominent bioactive component from Atractylodes macrocephala, exhibits powerful anticancer potentials in various malignancies. Nevertheless, the ATR-I's activity on CRPC has not been reported.
An enzalutamide-resistant (EnzR) cell line was successfully constructed. CCK-8, EdU, wound healing, Transwell assays, flow cytometry, and xenograft tumor models were applied to investigate the antitumor activity of ATR-I against CRPC. The changes in the gene expression profiles after ATR-I treatment were analyzed using RNA sequencing.
ATR-I suppressed the proliferative and migratory abilities of AR and AR CRPC cells, while triggering cell cycle arrest and apoptosis. ATR-I also exerted anti-cancer activity on EnzR cell lines. Intriguingly, a combination of ATR-I with enzalutamide synergistically induced more apoptosis of tumor cells. RNA-sequencing identified kinesin family member 15 (KIF15) as a potential target of ATR-I. KIF15 was up-regulated in prostate cancer (PCa), and its higher level was associated with poorer clinical outcomes. Further investigation showed that ATR-I mediated ubiquitin-proteasomal degradation of AR/AR-V7 through targeting KIF15, resulting in CRPC repression. Finally, our in vivo experiment verified that ATR-I alone or in combination with enzalutamide retarded the growth of EnzR xenograft tumors.
These findings identified ATR-I as a promising therapeutic drug for overcoming enzalutamide resistance in CRPC patients and increased our understanding about its antitumor mechanisms.
去势抵抗性前列腺癌（CRPC）一直是全球男性肿瘤相关死亡的主要原因。发现用于CRPC的新型治疗药物仍然至关重要。白术内酯I（ATR-I）是白术的一种重要生物活性成分，在各种恶性肿瘤中显示出强大的抗癌潜力。然而，ATR-I对CRPC的活性尚未见报道。
成功构建了恩杂鲁胺耐药（EnzR）细胞系。采用CCK-8、EdU、伤口愈合、Transwell实验、流式细胞术和异种移植瘤模型研究ATR-I对CRPC的抗肿瘤活性。使用RNA测序分析ATR-I处理后基因表达谱的变化。
ATR-I抑制AR和AR CRPC细胞的增殖和迁移能力，同时引发细胞周期停滞和凋亡。ATR-I对EnzR细胞系也具有抗癌活性。有趣的是，ATR-I与恩杂鲁胺联合使用可协同诱导更多肿瘤细胞凋亡。RNA测序确定驱动蛋白家族成员15（KIF15）为ATR-I的潜在靶点。KIF15在前列腺癌（PCa）中上调，其较高水平与较差的临床结果相关。进一步研究表明，ATR-I通过靶向KIF15介导AR/AR-V7的泛素-蛋白酶体降解，从而抑制CRPC。最后，我们的体内实验证实，ATR-I单独或与恩杂鲁胺联合使用可延缓EnzR异种移植瘤的生长。
这些发现确定ATR-I是一种有前途的治疗药物，可克服CRPC患者的恩杂鲁胺耐药性，并增加了我们对其抗肿瘤机制的理解。
