MDMX enhances radiosensitivity in lung adenocarcinoma and squamous cell carcinoma by inhibiting P53-mediated autophagy.

Objective: Radioresistance is a common cause of poor radiation therapy effectiveness for non-small cell lung cancer. Finding molecular targets or methods to enhance radiosensitivity or overcome radioresistance is crucial. This study aimed to investigate the effects of MDMX on modulating radiosensitivity in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

Methods: The expression of MDMX and its correlation with radiotherapy response were analyzed in 101 LUAD and LUSC patient samples. LUAD and LUSC cell lines (A549, SK-MES-1) and their radioresistant counterparts (A549R, SK-MES-1R) were used to assess the effects of MDMX and P53 on radiosensitivity through autophagy by using molecular assays and animal models.

Results: The expression of MDMX was decreased, but the autophagy was enhanced in radioresistant LUAD and LUSC cells. Overexpression of MDMX inhibited P53 activity, leading to autophagy suppression and increasing radiosensitivity. In contrast, P53 upregulation counteracted the effects of MDMX, resulting in increasing autophagy and radioresistance. The higher MDMX expression was associated with improved radiotherapy response and prolonged overall survival in LUAD and LUSC cells. The 5-year survival rate was 93.62% in the low MDMX expression group and 98.11% in the high MDMX expression group (P < 0.01).

Conclusion: MDMX enhances LUAD and LUSC radiosensitivity by downregulating P53-mediated autophagy. High MDMX expression correlated with better clinical outcomes, suggesting that MDMX could be a potential biomarker for predicting radiotherapy response and prognosis in LUAD and LUSC patients.