Zhai Chunmei, Sun Xiaorong, Zhang Song, Xing Ligang
Shandong Provincial Key Laboratory of Precision Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, Shandong, China.
Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Cell Death Dis. 2025 Apr 6;16(1):256. doi: 10.1038/s41419-025-07604-1.
Radiotherapy, as a vital means of esophageal cancer treatment, has benefited countless cancer patients, but owing to the occurrence of radio-resistance, its therapeutic efficiency has been dramatically mitigated. Discovering key biomarkers governing radio-tolerance in esophageal cancer and revealing their inherent molecular mechanisms will be of great significance for clinical cancer treatment. Here, we have found roundabout guidance receptor 1 (ROBO1) was significantly upregulated in esophageal cancerous tissues and showed enhanced expression with the development of cancer staging. Cellular experiments demonstrated ROBO1 directly interacted with eukaryotic translation initiation factor 3A (eIF3A) and accelerated its degradation in esophageal cancer cells after irradiation treatment. Mass spectrum analysis further revealed that in response to irradiation, ROBO1, eIF3A and G3BP2 (Ras GTPase-activating protein-binding protein 2) formed a hetero-complex and triggered lysosomes-mediated protein degradation. Knocking down of G3BP2 abrogated the influence of ROBO1 on eIF3A instability. Besides, ROBO1-mediated eIF3A degradation interrupted P53 translation process which in turn provoked downstream mTOR signaling and increased DNA repair associated genes expressions, resulting in radio-resistance enhancement in cancer cells. In conclusion, our findings revealed a novel role of eIF3A in modulating P53/mTOR signaling activity and provided a drug candidate (ROBO1) for overcoming radio-resistance in esophageal cancer.
放射治疗作为食管癌治疗的重要手段，已使无数癌症患者受益，但由于放射抗性的出现，其治疗效果已大幅降低。发现食管癌中控制放射耐受性的关键生物标志物并揭示其内在分子机制对临床癌症治疗具有重要意义。在此，我们发现食管癌组织中迂回引导受体1（ROBO1）显著上调，且随着癌症分期的发展其表达增强。细胞实验表明，ROBO1在照射处理后直接与真核翻译起始因子3A（eIF3A）相互作用，并加速其在食管癌细胞中的降解。质谱分析进一步显示，在照射后，ROBO1、eIF3A和G3BP2（Ras GTP酶激活蛋白结合蛋白2）形成异源复合物并触发溶酶体介导的蛋白质降解。敲低G3BP2可消除ROBO1对eIF3A不稳定性的影响。此外，ROBO1介导的eIF3A降解中断了P53翻译过程，进而激活下游mTOR信号并增加DNA修复相关基因的表达，导致癌细胞放射抗性增强。总之，我们的研究结果揭示了eIF3A在调节P53/mTOR信号活性中的新作用，并为克服食管癌放射抗性提供了一种候选药物（ROBO1）。
