Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage.
Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage.
复制标题
DOI：
10.1038/ncomms10112
复制
发表时间：
2015-12-11
影响因子：
16.6
通讯作者：
Rubinstein M
中科院分区：
文献类型：
--
作者：
Dvash E;Har-Tal M;Barak S;Meir O;Rubinstein M
内质网（ER）应激和主要化疗药物通过产生活性氧（ROS）损伤DNA。本研究表明，内质网应激和化疗通过转录上调和激活非造血谱系细胞中的微体谷胱甘肽- s -转移酶2 （MGST2）诱导白三烯C4 （LTC4）的生物合成。内质网应激和化疗也会触发两个LTC4受体的核易位。LTC4以胞内方式作用，引发NADPH氧化酶4 （NOX4）的核易位、ROS积累和氧化性DNA损伤。Mgst2缺乏、RNAi和LTC4受体拮抗剂在体外和小鼠肾脏中消除内质网应激和化疗诱导的ROS和氧化DNA损伤。细胞死亡和小鼠发病率也显著降低。因此，mgst2产生的LTC4是内质网应激和化疗引发的氧化应激和氧化DNA损伤的主要介质。LTC4抑制剂通常用于哮喘，可广泛用于与内质网应激激活NOX4相关的主要人类病理。化疗药物引起内质网和氧化应激是其作用模式的一部分。在这里，作者表明化疗和内质网应激触发基于mgst2的LTC4生物合成，其抑制消除化疗和内质网应激引发的氧化应激和DNA损伤，导致细胞死亡的衰减。
Endoplasmic reticulum (ER) stress and major chemotherapeutic agents damage DNA by generating reactive oxygen species (ROS). Here we show that ER stress and chemotherapy induce leukotriene C4 (LTC4) biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2) in cells of non-haematopoietic lineage. ER stress and chemotherapy also trigger nuclear translocation of the two LTC4 receptors. Acting in an intracrine manner, LTC4 then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage. Mgst2 deficiency, RNAi and LTC4 receptor antagonists abolish ER stress- and chemotherapy-induced ROS and oxidative DNA damage in vitro and in mouse kidneys. Cell death and mouse morbidity are also significantly attenuated. Hence, MGST2-generated LTC4 is a major mediator of ER stress- and chemotherapy-triggered oxidative stress and oxidative DNA damage. LTC4 inhibitors, commonly used for asthma, could find broad clinical use in major human pathologies associated with ER stress-activated NOX4. Chemotherapeutic agents elicit ER and oxidative stress as part of their mode of action. Here the authors show that chemotherapy and ER stress trigger MGST2-based biosynthesis of LTC4, whose inhibition abolishes chemotherapy- and ER stress-triggered oxidative stress and DNA damage, resulting in the attenuation of cell death.