Zheng Chanjuan, Yao Hui, Lu Lu, Li Hongqi, Zhou Lei, He Xueyan, Xu Xi, Xia Hongzhuo, Ding Siyu, Yang Yiyuan, Wang Xinyu, Wu Muyao, Xue Lian, Chen Sisi, Peng Xiaojun, Cheng Zhongyi, Wang Yian, He Guangchun, Fu Shujun, Keller Evan T, Liu Suling, Jiang Yi-Zhou, Deng Xiyun
Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China.
Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China.
Int J Biol Sci. 2024 Mar 18;20(6):2130-2148. doi: 10.7150/ijbs.94058. eCollection 2024.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，目前有效的治疗选择有限。我们之前已经证明，洛伐他汀（一种经美国食品药品监督管理局批准的降脂药物）能选择性抑制TNBC的干性特征。然而，洛伐他汀在TNBC中的细胞内靶点仍 largely未知。在此，我们意外地发现核糖体生物合成是洛伐他汀在TNBC中靶向的主要途径。洛伐他汀诱导核糖体生物合成相关蛋白的转位，包括核磷蛋白（NPM）、核仁及卷曲体磷蛋白1（NOLC1）和核糖体蛋白RPL3。洛伐他汀还抑制rRNA的转录水平，并增加核蛋白水平以及p53（核仁应激的主要调节因子）的转录活性。由10个核糖体生物合成相关基因生成的预后模型在预测TNBC患者的生存方面表现出色。线粒体核糖体蛋白S27（MRPS27）是风险模型基因排名最高的，在TNBC中高表达，且与肿瘤分期和淋巴结受累相关。从机制上讲，敲低MRPS27可抑制TNBC的干性特征和恶性表型。MRPS27的过表达减弱了洛伐他汀对TNBC细胞干性的抑制作用。我们的研究结果表明，核糖体生物合成失调是一个可靶向的弱点，靶向MRPS27可能是TNBC患者的一种新治疗策略。
