title: Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Dvash
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Har-Tal
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Barak
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Meir
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Menachem
authors.initials: M
authors.lastname: Rubinstein
mesh_terms: D000818:Animals; D020126:Brefeldin A / Q000633:toxicity; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D017997:Leukotriene C4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D034622:RNA Interference; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D014415:Tunicamycin; D020126:Brefeldin A; D017997:Leukotriene C4; D005982:Glutathione Transferase; C000607998:MGST2 protein, mouse; C041116:leukotriene-C4 synthase