ROBO1 enhanced esophageal carcinoma cell radioresistance through accelerating G3BP2-mediated eIF3A degradation

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.