Journal Article

Atractylenolide I ameliorated the growth and enzalutamide resistance of castration-resistant prostate cancer by targeting KIF15

Deng, Yuxuan, Hu, Peng, Liu, Xiaming, Hu, Bintao, Yang, Bin, Han, Chenglin, Wang, Tao, Yuan, Huixing, Li, Chengbao, Liu, Jihong

2025

Overview

Background 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. Methods 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. Results 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. Conclusions 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. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acupuncture / Androgens / Antibodies / Antigens / Antitumor activity / Apoptosis / AR/AR-V7 / ATR-I / B cells / Biology / Cancer / Care and treatment / Castration / Cell cycle / Cholecystokinin / Complementary & Alternative Medicine / CRPC / FDA approval / Flow cytometry / Gene amplification / Gene expression / Genes / Growth / KIF15 / Kinesin / Malignancy / Medical prognosis / Medicine / Medicine & Public Health / Phosphatase / Prostate cancer / Proteasomes / Proteins / RNA / RNA sequencing / Traditional Chinese Medicine / Tumor cell lines / Tumor cells / Tumors / Ubiquitin / Ubiquitin-proteasomal degradation / Wound healing / Xenografts