Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death
Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death
复制标题
线粒体 DNA 应激引发自噬依赖性铁死亡
DOI：
10.1080/15548627.2020.1739447
复制
发表时间：
2020-03-19
期刊：
影响因子：
13.3
通讯作者：
Tang, Daolin
中科院分区：
文献类型：
--
作者：
Li, Changfeng;Zhang, Ying;Tang, Daolin
摘要胰腺癌对目前的治疗有很高的抵抗力，5年生存率很低，仍然是生物医学的一大挑战。在这里，我们报告说，扎西他滨，人类免疫缺陷病毒感染的抗病毒药，可以通过诱导铁凋亡，铁依赖性形式的调节细胞死亡抑制原发性和永生化的人胰腺癌细胞的生长。从机制上讲，这种作用依赖于扎西他滨诱导的线粒体DNA应激，其激活STING 1/TMEM 173介导的DNA传感途径，导致通过脂质过氧化导致大自噬/自噬依赖性铁凋亡细胞死亡，而不是I型干扰素应答。因此，自噬依赖性铁凋亡途径的遗传和药理学失活减少了扎西他滨在细胞培养和动物模型中的抗癌作用。总之，这些发现不仅为胰腺癌治疗提供了一种新的方法，而且还增加了我们对自噬和DNA损伤反应在塑造细胞死亡中的相互作用的理解。缩略语：ALOX：花生四烯酸脂氧化酶; ARNTL/BMAL1：芳香烃受体核转位样; ATM：ATM丝氨酸/苏氨酸激酶; ATG：自噬相关; cGAMP：环GMP-AMP; CGAS：环GMP-AMP合酶; ER：内质网; FANCD 2：FA互补组D2; GPX 4：谷胱甘肽过氧化物酶4; IFNA 1/IFNα：干扰素α 1; IFNB 1/IFNβ：干扰素β 1; MAP 1 LC 3B/LC 3：微管相关蛋白1轻链3 β; MDA：丙二醛;线粒体DNA：线粒体DNA; NCOA4：核受体共激活因子4; PDAC：胰腺导管腺癌; POLG：DNA聚合酶γ，催化亚基; qRT-PCR：定量聚合酶链反应; RCD：调节性细胞死亡; ROS：活性氧; SLC 7A 11：溶质载体家族7成员11; STING 1/TMEM 173：干扰素应答刺激因子cGAMP相互作用因子1; TFAM：转录因子A，线粒体
ABSTRACT Pancreatic cancer tends to be highly resistant to current therapy and remains one of the great challenges in biomedicine with very low 5-year survival rates. Here, we report that zalcitabine, an antiviral drug for human immunodeficiency virus infection, can suppress the growth of primary and immortalized human pancreatic cancer cells through the induction of ferroptosis, an iron-dependent form of regulated cell death. Mechanically, this effect relies on zalcitabine-induced mitochondrial DNA stress, which activates the STING1/TMEM173-mediated DNA sensing pathway, leading to macroautophagy/autophagy-dependent ferroptotic cell death via lipid peroxidation, but not a type I interferon response. Consequently, the genetic and pharmacological inactivation of the autophagy-dependent ferroptosis pathway diminishes the anticancer effects of zalcitabine in cell culture and animal models. Together, these findings not only provide a new approach for pancreatic cancer therapy but also increase our understanding of the interplay between autophagy and DNA damage response in shaping cell death. Abbreviations: ALOX: arachidonate lipoxygenase; ARNTL/BMAL1: aryl hydrocarbon receptor nuclear translocator-like; ATM: ATM serine/threonine kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; ER: endoplasmic reticulum; FANCD2: FA complementation group D2; GPX4: glutathione peroxidase 4; IFNA1/IFNα: interferon alpha 1; IFNB1/IFNβ: interferon beta 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MDA: malondialdehyde; mtDNA: mitochondrial DNA; NCOA4: nuclear receptor coactivator 4; PDAC: pancreatic ductal adenocarcinoma; POLG: DNA polymerase gamma, catalytic subunit; qRT-PCR: quantitative polymerase chain reaction; RCD: regulated cell death; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; STING1/TMEM173: stimulator of interferon response cGAMP interactor 1; TFAM: transcription factor A, mitochondrial