Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase.
Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase.
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DOI：
10.1016/j.freeradbiomed.2022.10.004
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发表时间：
2022-10
影响因子：
7.4
通讯作者：
Shanlong Zhang;Li Kang;Xiaoxue Dai;Junlan Chen;Zhengtao Chen;Meixiang Wang;Huantong Jiang;X. Wang;Suqin Bu;Xinyuan Liu;Guohui Zhang;Hua Tang
中科院分区：
文献类型：
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作者：
Shanlong Zhang;Li Kang;Xiaoxue Dai;Junlan Chen;Zhengtao Chen;Meixiang Wang;Huantong Jiang;X. Wang;Suqin Bu;Xinyuan Liu;Guohui Zhang;Hua Tang
铁下垂是一种新的调节性细胞死亡形式，其特征是铁依赖的过氧化脂质积聚到致死水平，在形态上、生化上和遗传学上都不同于细胞凋亡、坏死性下垂、自噬和下垂。锰在天然免疫和抗肿瘤免疫中发挥着重要作用。许多锰基纳米材料通过催化肿瘤内活性氧簇(ROS)的产生来诱导肿瘤细胞死亡。然而，确切的潜在机制仍不清楚。随着肿瘤中铁下垂研究的不断深入及其调控机制的不断完善，越来越多的证据表明，在肿瘤细胞中触发铁下垂是治疗肿瘤的有效策略。在本研究中，我们发现，给肿瘤细胞注射MnCl2会导致脂质过氧化，增加线粒体ROS水平，从而导致铁性下垂。二氢罗酸脱氢酶(DHODH)介导的铁下垂防御是癌症中的一个靶向易损性。我们发现，MnCl2下调肿瘤细胞中DHODH的表达，导致线粒体ROS和脂质过氧化增加，从而诱导铁性下垂。此外，MnCl2还提高了STIN、TBK1和IRF3的磷酸化水平，上调了cGAS-STING信号通路产生的I型干扰素(IFN)的表达。当抑制cGAS-STING信号通路或I型干扰素时，DHODH的表达恢复，逆转脂质过氧化和ROS的产生，挽救MnCl2诱导的铁下垂。敲除IFNAR1或过表达DHODH可减弱MnCl2的抗肿瘤作用。从机制上讲，这些结果表明，锰处理激活的cGAS-STING信号通过释放I型IFN来促进线粒体脂质过氧化和ROS的产生，从而降低DHODH功能，从而诱导肿瘤细胞铁下垂。这可能为补充现有的抗肿瘤治疗方案提供一种新的策略。
Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl2to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl2downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl2enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS–STING signaling pathway. When inhibiting the cGAS–STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl2-induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl2. Mechanistically, these results revealed that Manganese treatment-activated cGAS–STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.