Wei Yuyan, Liu Fengying, Zhu Xialin, Liu Xiaoting, Li Hongxing, Hou Liujing, Ma Xiaoli, Li Fei, Liu Hongyan
Jinan Central Hospital, Shandong First Medical University, Jinan 250013, Shandong, China.
State Key Laboratory of Biobased Material and Green Papermaking, School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
Phytomedicine. 2025 Jan;136:156333. doi: 10.1016/j.phymed.2024.156333. Epub 2024 Dec 20.
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.
This study aims to reveal the novel role of artesunate (ART), a well-known antimalarial drug, in suppressing ribosome RNA biogenesis in ovarian cancer.
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.
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 and the assembly of ribosome precursors with ribosomal proteins, other closely-related proteins and small nucleolar RNAs. We observed that ART inhibited the nuclear translocation of FANCA through binding to FANCA protein, consequently leading to the inhibition of ribosome RNA synthesis. Moreover, knockdown of FANCA in ovarian tumor cells resulted in reduced rRNA transcription, suppressed cell proliferation and migration, and induced apoptosis which might be mediated through the inhibition of mTOR/RPS6 activity. In vivo studies using xenograft tumors in nude mice demonstrated that ART repressed the growth of established ovarian cancer tumors. Additionally, ART treatment significantly altered FANCA protein level in these tumors, especially suppressed its nuclear localization.
These findings establish ART as a potent inhibitor of ribosome biogenesis, presenting a promising therapeutic avenue for ovarian tumors with high FANCA expression or for cancer patients exhibiting abnormal activation of the mTOR-RPS6 pathway.
核糖体生物发生失调在多种癌症中已被广泛发现，使其成为恶性细胞的一个标志。这凸显了将核糖体生物发生作为治疗癌症患者的有效方法的潜力。尽管包括阿霉素和顺铂在内的化疗药物常常靶向核糖体生物发生以诱导DNA损伤或抑制肿瘤细胞增殖，但它们会产生显著的副作用。
本研究旨在揭示著名的抗疟药物青蒿琥酯（ART）在抑制卵巢癌核糖体RNA生物发生中的新作用。
在本研究中，对青蒿琥酯抑制卵巢癌的作用进行了体外和体内研究。通过5-乙炔基尿苷染色、RT-qPCR和蛋白质免疫印迹法检测青蒿琥酯对核糖体RNA生物发生的影响。将药物亲和力响应靶点稳定性、质谱分析、分子对接和蛋白质免疫印迹法相结合以鉴定青蒿琥酯的分子靶点。
用青蒿琥酯处理的卵巢癌细胞新生rRNA合成显著减少，同时前体rRNA和成熟rRNA表达明显下调。青蒿琥酯对核糖体生物发生的抑制作用随后损害了细胞增殖、细胞迁移和侵袭，并诱导了细胞凋亡。在真核生物中，核糖体RNA合成主要发生在细胞核中，涉及rDNA转录、前体rRNA剪接以及核糖体前体与核糖体蛋白、其他密切相关蛋白和小核仁RNA的组装等过程。我们观察到青蒿琥酯通过与FANCA蛋白结合抑制了FANCA的核转位，从而导致核糖体RNA合成受到抑制。此外，敲低卵巢肿瘤细胞中的FANCA会导致rRNA转录减少、细胞增殖和迁移受到抑制，并诱导细胞凋亡，这可能是通过抑制mTOR/RPS6活性介导的。使用裸鼠异种移植瘤的体内研究表明，青蒿琥酯可抑制已形成的卵巢癌肿瘤的生长。此外，青蒿琥酯治疗显著改变了这些肿瘤中FANCA蛋白水平，尤其抑制了其核定位。
这些发现确立了青蒿琥酯作为核糖体生物发生的有效抑制剂，为FANCA高表达的卵巢肿瘤或mTOR-RPS6通路异常激活的癌症患者提供了一条有前景的治疗途径。
