PDF(Pubmed)
Abstract：
BACKGROUND: Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation.
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.
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.
摘要：
背景：靶向DNA损伤修复因子，如DNA依赖性蛋白激酶催化亚基（DNA-PKcs），可能提供有效治疗多发性骨髓瘤（MM）的机会。结合DNA损伤诱导剂，该策略已被证明可以通过升高的细胞溶质DNA水平激活cGAS-STING途径来部分改善化疗。然而,由于cGAS主要被细胞核中的染色质隔离，目前尚不清楚cGAS如何在DNA损伤后从染色质中释放并易位到细胞质中，导致cGAS-STING激活。
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。
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。
