Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage

• Published in: Nature communications Vol. 6; no. 1; p. 10112
• Main Authors: Dvash, Efrat, Har-Tal, Michal, Barak, Sara, Meir, Ofir, Rubinstein, Menachem
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2015; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/44; 13/51; 13/89; 14/19; 14/34; 14/63; 38; 38/77; 631/337/1427; 631/67/1059/99; 631/80/2023/2022; 631/80/86/2366; 64/60; 82/29; 82/80; 96/44; Animals; Apoptosis; Asthma; Biosynthesis; Brefeldin A - toxicity; Cell death; Cell Survival; Cells, Cultured; Chemotherapy; DNA Damage; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzymes; Gene Expression Regulation - physiology; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Humanities and Social Sciences; Humans; Kidney Diseases - chemically induced; Leukotriene C4 - genetics; Leukotriene C4 - metabolism; Localization; Mice; Mice, Knockout; multidisciplinary; Oxidative Stress; Physiology; Proteins; RNA Interference; Science; Science (multidisciplinary); Tunicamycin - toxicity; Israel
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10112

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 C 4 (LTC 4 ) 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 LTC 4 receptors. Acting in an intracrine manner, LTC 4 then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage. Mgst 2 deficiency, RNAi and LTC 4 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 LTC 4 is a major mediator of ER stress- and chemotherapy-triggered oxidative stress and oxidative DNA damage. LTC 4 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 LTC 4 , whose inhibition abolishes chemotherapy- and ER stress-triggered oxidative stress and DNA damage, resulting in the attenuation of cell death.