Artesunate disrupts ribosome RNA biogenesis and inhibits ovarian cancer growth by targeting FANCA

作者：Yuyan Wei, Fengying Liu, Xialin Zhu, Xiaoting Liu, Hongxing Li, Liujing Hou, Xiaoli Ma, Fei Li, Hongyan Liu · 发表于：Phytomedicine · 年份：2024 · DOI：10.1016/j.phymed.2024.156333 · 被引用次数：16 · 研究领域：RNA modifications and cancer、Cancer, Lipids, and Metabolism、Ubiquitin and proteasome pathways

BACKGROUND: The dysregulation of ribosome biogenesis has been extensively identified in various cancers, making it emerge as a hallmark of malignant cells. This highlights the potential of targeting ribosome biogenesis as an effective approach for treating cancer patients. Although chemotherapy drugs including doxorubicin and cisplatin often target ribosome biogenesis to induce DNA damage or inhibit tumor cell proliferation, they are associated with significant side effects. PURPOSE: This study aims to reveal the novel role of artesunate (ART), a well-known antimalarial drug, in suppressing ribosome RNA biogenesis in ovarian cancer. METHODS: In this study, the inhibitory effects of ART on ovarian cancer were studied both in vitro and in vivo. The effects of ART on ribosome RNA biogenesis were detected by 5-ethynyl uridine staining, RT-qPCR, and western blotting. Drug affinity responsive target stability, mass spectrometry, molecular docking and western blotting were combined to identify ART molecular targets. RESULTS: Ovarian cancer cells treated with ART exhibited significant reduction in nascent rRNA synthesis, accompanied by a remarkable down-regulation of pre-rRNA and mature rRNA expression. The inhibitory effect of ART on ribosome biogenesis subsequently impaired cell proliferation, cell migration and invasion, and induced apoptosis. In eukaryotes, ribosome RNA synthesis primarily occurs in the nucleus, involving processes such as rDNA transcription, pre-rRNA splicing an...