A pathway to stress

Nat. Commun. 6, 10112 (2015)

Chemotherapy is known to trigger oxidative DNA damage and reactive oxygen species (ROS)-mediated cell death, which can cause harmful side effects. Because leukotriene C₄ (LCT₄)—a signaling molecule best known for being secreted by mast cells during allergic reactions—had previously been shown to trigger cellular ROS accumulation, Dvash et al. decided to investigate the potential role of LCT₄ production in the oxidative stress response in non-hematopoietic cells. The authors' initial observation was that enzymes involved in leukotriene biosynthesis, including glutathione S-transferase 2 (MGST2), are upregulated and accumulate in the nucleus in response to endoplasmic reticulum (ER) stress, triggering LCT₄ production. This synthetic pathway is distinct from that found in hematopoietic cell lineages, which uniquely express LCT₄ synthase, an MGST2 isozyme. The authors then demonstrated that LCT₄ accumulation mediates chemotherapeutic agent–triggered oxidative damage and that the cytotoxicity of those treatments can be greatly reduced in mouse models by interfering with the production or action of LCT₄—either through Mgst2 deficiency or through the application of LCT₄ antagonists commonly used in asthma treatment. In addition to uncovering a novel pathway to LCT₄ biosynthesis in non-hematopoietic cells triggered by ER stress, the work suggests potential clinical applications for LCT₄ antagonists in mediating the side effects of cytotoxic chemotherapy.