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Targeting castration-resistant prostate cancer with a novel ROR? antagonist elaiophylin

ABSTRACT: Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR? as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from Actinomycete streptomyces, is a novel ROR? antagonist and showed potent antitumor activity against CRPC in vitro and in vivo. We demonstrated that Elai selectively binded to ROR? protein and potently blocked ROR? transcriptional regulation activities. Structure–activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of ROR? to its genomic DNA response element (RORE), suppressed the expression of ROR? target genes AR and AR variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic ROR? inhibitor that can be used as a drug candidate for the treatment of human CRPC. Graphical abstract Elaiophylin was identified as a novel and potent ROR? antagonist. It strongly inhibits androgen receptor (AR) expression and cell autophagy via suppressing ROR? activity, and shows robust antitumor activity against CRPC in vitro and in vivo.Image 1

SUBMITTER: Zheng J

PROVIDER: S-EPMC7745055 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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