Department of Clinical Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing 400038, China; Department of Clinical Hematology, College of Pharmacy, Army Medical University, Chongqing 400038, China; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China.
Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China.
Int Immunopharmacol. 2024 Sep 30;139:112672. doi: 10.1016/j.intimp.2024.112672. Epub 2024 Jul 19.
The resistance of osteosarcoma (OS) to ionizing radiation (IR) is an obstacle for effective patient treatment. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. We previously revealed the role of APE1 in OS radioresistance; however, whether the redox activity of APE1 is involved in OS radioresistance is unclear. APE1 regulates the activation of ataxia-telangiectasia mutated (ATM), an initiator of DNA damage response that mediates radioresistance in other cancers. The role of APE1 redox activity and ATM activation in OS radioresistance is unknown. Our study revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The combined use of an APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR in vitro and in vivo. Mechanistically, the increased radiosensitization of OS cells by the combined use of the two inhibitors was mediated by increased ferroptosis. Co-treatment with the two inhibitors significantly decreased expression of the common targeted transcription factor P53 compared with single inhibitor treatment. Collectively, APE1 redox activity, ATM activation and their crosstalk play important roles in the resistance of OS to irradiation. Synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which provides a promising strategy for OS radiotherapy.
骨肉瘤（OS）对电离辐射（IR）的耐药性是有效治疗患者的障碍。脱嘌呤/脱嘧啶核酸内切酶修复/氧化还原因子 1（APE1/Ref-1）是一种具有 DNA 修复和氧化还原（redox）活性的多功能蛋白。我们之前揭示了 APE1 在 OS 放射抵抗中的作用；然而，APE1 的氧化还原活性是否参与 OS 放射抵抗尚不清楚。APE1 调节共济失调毛细血管扩张突变（ATM）的激活，ATM 是其他癌症中介导放射抵抗的 DNA 损伤反应的启动子。APE1 氧化还原活性和 ATM 激活在 OS 放射抵抗中的作用尚不清楚。我们的研究表明，IR 增加了 OS 细胞中 APE1 的表达和 ATM 的激活，APE1 通过其氧化还原活性直接调节 ATM 的激活。APE1 氧化还原抑制剂和 ATM 抑制剂的联合使用有效地增强了 OS 细胞在体外和体内对 IR 的敏感性。从机制上讲，两种抑制剂联合使用增加了 OS 细胞的放射增敏性，这是由铁死亡的增加介导的。与单抑制剂处理相比，两种抑制剂的共同处理显著降低了常见靶向转录因子 P53 的表达。总之，APE1 氧化还原活性、ATM 激活及其相互作用在 OS 对辐射的耐药性中起重要作用。协同抑制 APE1 氧化还原活性和 ATM 激活通过诱导铁死亡使 OS 细胞对 IR 敏感，为 OS 放射治疗提供了一种有前途的策略。
