Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (MDA-MB-231)

Radiotherapy (RT) reduces the risk of cancer recurrence and death, while accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles (sEVs) to trigger skeletal muscle weakness upon RT. Mechanistically, RT-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of SRM protein, facilitating SRM packaging into EVs from primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon RT, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of RT-mediated muscle weakness when combined with losartan treatment. Comparative gene expression profiling analysis of RNA-seq data for RT-treated and non-treated MDA-MB-231 cells

放射治疗（Radiotherapy, RT）可降低癌症复发与死亡风险，且伴随肌肉纤维化、肌无力等多种不良反应，严重降低患者生活质量。但其潜在分子机制尚不清楚。本研究发现，肿瘤细胞可通过小型细胞外囊泡（small extracellular vesicles, sEVs）分泌更多亚精胺合酶（spermidine synthase, SRM），在放射治疗后诱发骨骼肌无力。机制层面，放射治疗诱导的花生四烯酸（arachidonic acid, ArA）积累可提升SRM蛋白的ISG化修饰水平，促进SRM被包装入原发肿瘤来源的细胞外囊泡。循环系统中的SRM可通过依赖真核翻译起始因子5A（eIF5A）的途径，促使骨骼肌内亚精胺积累并启动I型胶原纤维的生物合成。而氯沙坦（losartan）处理可阻断SRM的ISG化修饰及其后续分泌过程。综上，本研究证实：放射治疗后，花生四烯酸可协同促进循环SRM的分泌，通过重编程多胺代谢加重骨骼肌纤维化，为联合氯沙坦治疗以缓解放射治疗诱导的肌无力提供了新的理论依据。本研究同时对经放射治疗处理与未处理的MDA-MB-231细胞的RNA测序数据开展了比较基因表达谱分析。