METHODS: We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study.
RESULTS: Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING.
CONCLUSIONS: Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.
方法:我们通过进行质谱和机制研究,检查了DNA-PKcs抑制对cGAS-STING介导的MM化学敏感性的作用。
结果:这里,我们发现DNA-PKcs抑制通过激活cGAS-STING信号增强DNA损伤诱导剂阿霉素诱导的抗MM作用。MM细胞中的cGAS-STING激活部分通过IRF3-NOXA-BAK轴引起细胞死亡,并诱导巨噬细胞的M1极化。此外,这种激活不是由经典的非同源末端连接(c-NHEJ)缺陷引起的。相反,多柔比星诱导的DNA损伤,抑制DNA-PKcs促进cGAS从细胞质染色质片段释放,并增加细胞溶质cGAS和DNA的量,激活cGAS-STING。
结论:抑制DNA-PKcs可以通过去螯合cGAS来改善多柔比星治疗MM的疗效。