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

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.

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