Shi Zhonggang, Zhao Jianyi, Lv Qi, Liao Keman, Cao Lu, Yang Jian, Wang Mengying, Zhou Li, Xu Haoping, Ge Jianwei, Qiu Yongming, Chen Juxiang, Chen Jiayi, Ma Chunhui, Lin Yingying
Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Proton-Therapy, Shanghai, China.
Bone Res. 2025 Aug 26;13(1):74. doi: 10.1038/s41413-025-00453-w.
Osteosarcoma (OS) is the most frequent primary bone sarcomas with high recurrence and poor prognosis. Emerging evidence indicates that membraneless organelles stress granules (SGs), whose assemblies are driven by scaffold protein G3BP1, are extensively involved in tumor, especially in OS. However, how SGs behave and communicate with organelles, particularly nucleoli and mitochondria, during drug challenges remain unknown. This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase (AEP) to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma. tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1. Strikingly, tG3BP1-Cs, containing a conserved RNA recognition motif CCUBSCUS, sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress. Moreover, the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs, whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models. Cancerous tissues exhibited high levels of AEP and G3BP1 truncations, which were strongly associated with poor prognosis. Accordingly, this study proposed a new paradigm and potential therapeutic targets to address chemotherapy sensitivity conferred by AEP-cleaved G3BP1-mediated SGs/nucleoli/mitochondria coordination.
骨肉瘤（OS）是最常见的原发性骨肉瘤，具有高复发率和不良预后。新出现的证据表明，无膜细胞器应激颗粒（SGs）由支架蛋白G3BP1驱动组装，广泛参与肿瘤发生，尤其是在OS中。然而，在药物攻击期间，SGs如何表现以及与细胞器，特别是核仁和线粒体进行通讯，仍然未知。本研究揭示，化疗药物激活半胱氨酸蛋白酶天冬酰胺内肽酶（AEP），以特异性切割OS和恶性胶质瘤中SG核心蛋白G3BP1的N258/N309位点。tG3BP1-Ns通过竞争性结合全长G3BP1来调节SG动态。引人注目的是，含有保守RNA识别基序CCUBSCUS的tG3BP1-Cs，在核仁和线粒体中隔离核糖体蛋白和氧化磷酸化基因的mRNA，以抑制翻译和氧化应激。此外，抑制AEP可增强化疗药物的肿瘤抑制作用, 而AEP切割的G3BP1拯救则逆转了OS和胶质瘤模型中的这种作用。癌组织表现出高水平的AEP和G3BP1截短体，这与不良预后密切相关。因此，本研究提出了一种新的范式和潜在治疗靶点，以解决由AEP切割的G3BP1介导的SGs/核仁/线粒体协调所赋予的化疗敏感性问题。
