Inhibition of AEBP1 predisposes cisplatin-resistant oral cancer cells to ferroptosis

Abstract Background Studies have shown that excessive iron can lead to an increased incidence of cancer. The role of adipocyte enhancer-binding protein 1 (AEBP1) on ferroptosis is unknown. Thus, we explored the effect of AEBP1 silencing in regulation of ferroptosis in cisplatin-resistant oral cancer cells. Methods The functions of AEBP1 silencing and sulfasalazine (SSZ) treatment were determined on oral cancer cell lines and tumor xenograft mouse models. Then we evaluated the functions of AEBP1 on cell proliferation, migration, invasion, lipid reactive oxygen species (ROS), labile iron pool (LIP) and free iron, lipid peroxidation, and expression levels of ferroptosis-related genes. Results AEBP1 was highly expressed in oral cancer cells and tissues. AEBP1 silencing inhibited oral cancer cell proliferation, migration, and invasion after SSZ treatment. SSZ-induced ferroptosis is due to enhanced ROS level, free iron, and lipid peroxidation, which were distinctly increased by AEBP1 silencing. Meanwhile, AEBP1 silencing enhanced the effects of SSZ on levels of LIP and Fe 2+ , lipid peroxidation, as well as the expression levels of ferroptosis-related genes in the tumor xenograft mouse models. Importantly, AEBP1 silencing suppressed tumor growth in vivo. Furthermore, silencing of AEBP1 might activate the JNK/ P38 /ERK pathway. Conclusion This research suggested that silencing of AEBP1 predisposes cisplatin-resistant oral cancer cells to ferroptosis via the JNK/p38 /ERK pathway.