The COX-2 Inhibitor Celecoxib Sensitizes Nasopharyngeal Carcinoma Cells to Ferroptosis

BACKGROUND: Nasopharyngeal cancer (NPC) is prevalent in Southeast Asia and North Africa, which is generally associated with limited treatment options and poor patient prognosis. OBJECTIVE: Ferroptosis is a recently observed cell death modality and has been shown to link to the efficacy of different anti-cancer treatments, thus offering opportunities to the development of novel therapies. This study aims to investigate the potentiating effects of COX-2 inhibitors on ferroptosis in nasopharyngeal cancer. METHODS: The inhibitory effects of COX-2 inhibitors celecoxib and rofecoxib on nasopharyngeal cancer cells were assessed with MTT, colony formation, sphere formation, Transwell, wound healing assays. The status of COX-2 with celecoxib and rofecoxib treatment was investigated by Western blotting and immunofluorescence experiments. Ferroptosis was induced with the GPX4 inhibitor RSL3 with or without COX-2 inhibition and was monitored by fluorescence microscopy. Transcriptomic profiling was conducted with 5-8F cells treated with DMSO as control or celecoxib, and ferroptosis-related candidates were validated by RT- PCR analysis. RESULTS: Celecoxib and rofecoxib effectively inhibited the growth and migration of nasopharyngeal cancer cells. Both inhibitors evidently sensitized nasopharyngeal cancer cells to ferroptosis induction by RSL3, with celecoxib outperforming rofecoxib. Celecoxib treatment resulted in significantly differentially expressed genes in 5-8F cells, among which CHAC1 was validated as a ferroptosis-related target. CONCLUSION: The COX-2 inhibitor celecoxib effectively sensitized nasopharyngeal cancer cells to ferroptosis induction.