GPR37-enhanced ubiquitination of ATP1A1 inhibits tumor progression and radiation resistance in esophageal squamous cell carcinoma

Radiotherapy resistance is one of the main reasons for the dismal clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). Therefore, clarifying the targets and molecular mechanisms of radiotherapy resistance in ESCC is of great theoretical and clinical significance to enhance the efficacy of radiotherapy. In this study, GPR37 was identified as a key factor facilitating ESCC radiosensitization. We found that GPR37 is lowly expressed in ESCC, especially in radioresistant ESCC tumors. And its insufficiency is related to the malignant characteristics and unfavorable prognosis in ESCC. Further investigation revealed that GPR37 level is inversely regulated by promoter methylation but positively regulated by ZNF750. Functionally, GPR37 could not only overcome radioresistance of ESCC, but also inhibit proliferation, migration, and invasion. Mechanistically, GPR37 interacts with the ATP1A1 protein, effectively promoting its ubiquitination-induced degradation, thereby limiting the activation of the AKT/mTOR signaling pathway. Additionally, GPR37 can be transported to recipient cells via exosomes and inhibit the malignant behavior of recipient cells. Overall, these findings suggest that GPR37-ATP1A1 axis holds potential as a therapeutic target for the management of ESCC, especially for overcoming radiation resistance.