Mitochondrial APE1 promotes cisplatin resistance by downregulating ROS in osteosarcoma

Apurinic/apyrimidinic endonuclease 1 (APE1) is a primary nuclear-localized multifunctional protein in osteosarcoma. However, the cytoplasmic localization of APE1 was found to be functional and to increase with cisplatin resistance, yet the molecular mechanism is unknown. In the present study, we explored the cisplatin resistance mechanism in osteosarcoma from the new perspective of APE1 extranuclear biological activity. Using cisplatin-resistant and cisplatin-sensitive osteosarcoma cell lines, we found that mitochondrial APE1 (mtAPE1) was overexpressed in cisplatin-resistant cells but not in sensitive cells. Overexpression of mtAPE1 reduced cisplatin-induced apoptosis, while knockdown of APE1 reversed this phenomenon and caused oxidative DNA damage via overproduction of reactive oxygen species (ROS). We further demonstrated that high mtAPE1 expression could downregulate ROS production by decreasing the phosphorylation of Rac1 (p-Rac1), further promoting cisplatin resistance in osteosarcoma. Our findings suggest that mitochondrial APE1 promotes cisplatin resistance by decreasing ROS generation, which may provide new ideas for researching the molecular mechanism of osteosarcoma chemoresistance and strategies to overcome cisplatin resistance in osteosarcoma.