Atractylenolide I ameliorated the progression of CRPC by suppressing
Background and purpose: Castration-resistant prostate cancer (CRPC) has
been a major cause of tumor-associated death among men worldwide. The
discovery of novel therapeutic approaches 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 and its
underlying mechanism has not been reported. Experimental approach: An
enzalutamide-resistant (EnzR) cell line was successfully constructed.
The pharmacological effects of ATR-I were assessed in vitro and in vivo.
The changes in the gene expression profiles after ATR-I treatment were
analyzed using RNA sequencing (RNA-seq). Key results: ATR-I suppressed
the proliferative and migratory abilities of CRPC cells, while
triggering cell cycle arrest and apoptosis. In constructed EnzR cells,
ATR-I also inhibited their proliferation and promoted apoptosis.
Intriguingly, a combination of ATR-I with enzalutamide synergistically
induced more apoptosis of EnzR cells. Mechanistically, RNA-seq results
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 inhibited the expression of KIF15 mRNA
and protein, thus mediating ubiquitin-proteasomal degradation of
AR/AR-V7. Finally, our in vivo experiment verified that ATR-I alone or
in combination with enzalutamide retarded the growth of EnzR xenograft
tumors. Conclusion and implications: This study elucidated the antitumor
mechanism of ATR-I against CRPC. Notably, ATR-I may be a promising
therapeutic drug for CPRC patients and enhance the response to
enzalutamide in EnzR patients.