ANXA1 Binds and Stabilizes EGFR to Promote Nasopharyngeal Carcinoma Radioresistance

Radioresistance is a serious obstacle to successful nasopharyngeal carcinoma (NPC) treatment. Annexin A1 (ANXA1) is associated with EGFR and is involved in EGFR-promoting tumors, but the mechanisms of ANXA1-stabilizing EGFR and its effect on NPC radioresistance are unclear. In this study, we report that ANXA1 competes with the E3 ubiquitin ligase Cbl for binding to EGFR and increases its stability by inhibiting Cbl-mediated EGFR ubiquitination degradation in NPC cells. ANXA1 increases in vitro and in vivo NPC cell radioresistance by stabilizing EGFR. Expression levels of ANXA1 and EGFR are positively correlated in NPC tissues and are significantly higher in the radioresistant NPC tissues than in the radiosensitive NPC tissues. Patients with NPC with high expression of both proteins have poorer overall survival and disease-free survival relative to patients with high expression of one protein alone, and a combination of ANXA1 and EGFR predicts NPC radiosensitivity superior to that of the individual proteins. Based on the amino acid residues of ANXA1 responsible for binding to EGFR, we developed a nine amino acid-long ANXA1-derived peptide (HDMNKVLDL), which disrupts the connection of ANXA1 with EGFR, successfully downregulates EGFR expression, and dramatically increases NPC cell radiosensitivity in vitro and in mice. Our findings suggest that ANXA1 promotes NPC radioresistance by binding to and stabilizing EGFR, and we present a strategy for targeting EGFR degradation and NPC radiosensitization with a peptide.