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

  • Chin Med. 2025 Mar 14;20(1):35. doi: 10.1186/s13020-025-01086-1.
Chenglin Han  1 ,  Bin Yang  1 ,  Yuxuan Deng  1 ,  Peng Hu  1 ,  Bintao Hu  1 ,  Xiaming Liu  1 ,  Tao Wang  1 ,  Chengbao Li  2 ,  Jihong Liu  3 ,  Huixing Yuan  4
Affiliations
  • 1. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 2. Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 3. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. [email protected].
  • 4. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. [email protected].
PMID: 40087774 DOI: 10.1186/s13020-025-01086-1
Abstract

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.

Keywords
AR/AR-V7; ATR-I; CRPC; KIF15; Ubiquitin-proteasomal degradation.
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