Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma

Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we used a 3D suspension culture model combined with proteomic screening, identifying a relationship between dynamin-related protein 1 (Drp1) and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAM) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK-MFF-Drp1 and AMPK-mTOR-Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1-BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC. SIGNIFICANCE: Drp1 translocation to MAMs and interaction with BIP induces mitochondrial remodeling and anoikis resistance to support metastasis in NPC, highlighting the potential of Drp1 as a therapeutic target.