The Bystander Effect is a Novel Mechanism of UVA-Induced Melanogenesis

We successfully identified the bystander effect in B16 murine melanoma cells exposed to UVA irradiation. The effect was identified based on melanogenesis following the medium transfer of the B16 cells, which had been cultured for 24 h after being exposed to UVA irradiation, to nonirradiated cells (bystander cells). Our confirmation study of the functional mechanism of bystander cells confirmed the reduced levels of mitochondrial membrane potential 1–4 h after the medium transfer. In addition, we observed increased levels of intracellular oxidation after 9–12 h, and the generation of melanin radicals, including long‐lived radicals, 24 h after medium transfer. Further analysis of bystander factors revealed that the administration of EGTA treatment at the time of medium transfer led to an inhibition of melanogenesis and to neutralization of the mitochondrial membrane potential level, as well as to the restoration of intracellular oxidation levels to those of controls. The results demonstrated that the UVA irradiation bystander effect in B16 cells, as indicated by melanogenesis, was induced by the increase in intracellular oxidation due to the mitochondrial activity of calcium ions, which were among the bystander factors involved in the increase. The melanogenesis in UVA‐irradiated cell is promoted by bystander effect acting between melanocytes without contribution of the keratinocyte. The bystander factor such as Ca2+ decreases mitochondria membrane potential in a nonradiation cell and desorbs a large quantity of oxidation radicals to cytoplasm. As a result, intracellular level of oxidation increases, and the activation of melanogenesis genes occurs in nuclei. Melanogenesis by bystander effects is efficiently inhibited by treatment of EGTA.