Synergistic inhibition of APE1 redox activity and ATM activation sensitizes osteosarcoma cells to ionizing radiation by inducing ferroptosis

Abstract

The resistance of osteosarcoma (OS) to ionizing radiation (IR) is a great obstacle for its radiotherapy. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. Our previous study revealed a role of APE1 in OS radioresistance, but whether the redox activity of APE1 is involved is not clear. Moreover, APE1 has recently been shown to regulate ataxia-telangiectasia mutated(ATM) activation, which is an initiator of DNA damage response and mediates radioresistance in several other cancers. Although their role in radioresistance of OS remains to be studied, the possible crosstalk between APE1 redox activity and ATM activation may complicate the mechanism of OS radioresistance. Our results revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The synergetic administration of APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR. Further study revealed that ferroptosis mediated the radiosensitization of OS cells induced by the combined inhibition of APE1 redox activity and ATM activation. Moreover, simultaneous treatment withthese two inhibitors, rather than each alone, drastically decreased the expression of their common targeting transcription factor p53. Taken together, our results demonstrated that APE1 redox activity and ATM activation as well as their crosstalk played important roles in the resistance of OS to irradiation, and synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which providesa promising strategy for OS radiotherapy.