Abnormal circadian rhythms and neutrophil extracellular trap-associated cell death play a role in skin cancer caused by long-term blue light irradiation

Abstract Humans are exposed to large amounts of blue light from computers and smartphones. To date, no treatment has been developed for ameliorating nonmelanoma skin cancer induced by exposure to blue light. Here, we investigated the effects of tranexamic acid, carbazochrome, diisopropylamine dichloroacetate, and pantethine on blue light-induced skin cancer. The dorsal skin of male hairless mice was exposed to 40 kJ/m2 blue light thrice a week for 15 weeks after the application of 7,12-dimethylbenz[a]anthracene (DMBA). During the experimental period, mice were administered four types of test samples thrice a week. Skin cancer was induced in DMBA/blue light-treated mice, which improved upon administration of tranexamic acid or carbazochrome. In the mice treated with tranexamic acid or carbazochrome, the decrease in brain and muscle arnt-like 1 (Bmal1) level was suppressed, and the levels of neutrophils, beta 2 adrenergic receptor (β2-AR), intercellular adhesion molecule 1 (ICAM1), C-C motif chemokine ligand 2 (CCL2), and noradrenaline were affected by Bmal1. Furthermore, the administration of tranexamic acid and carbazochrome suppressed neutrophil extracellular trap-associated cell death (NETosis) caused by blue light irradiation. Hence, skin cancer induced by DMBA and blue light irradiation in mice can be improved by tranexamic acid or carbazochrome because tranexamic acid or carbazochrome modulates the noradrenaline/AR-β2/CCL2/ICAM1/neutrophil/NETosis signal transduction system regulated by the clock gene Bmal1.