Bystander effects induced by chemicals and ionizing radiation: evaluation of changes in gene expression of downstream MAPK targets.

Radiation-induced bystander effects have been evaluated extensively, including the involvement of the mitogen-activated protein kinase (MAPK) pathways. However, few studies have examined the ability of chemicals to induce bystander effects, and the molecular mechanisms involved in chemical bystander effects have not been investigated. We have previously demonstrated the ability of mitomycin C (MMC) and phleomycin (PHL) to induce bystander effects in normal human lymphoblastoid cells. Here, we demonstrate changes in the expression of MAPK target genes following bystander exposure to MMC or PHL or ionizing radiation. The expression changes of 18 genes, which code for proteins that are downstream targets of MAPK proteins, were evaluated at various time points following direct or bystander exposure to MMC, PHL and ionizing radiation. The 18 genes were analysed as groups belonging to one of the seven possible combinations of the three MAPK pathways. We observed statistically significant changes in expression of several genes following exposure to each agent. However, when the expression changes were analysed in the bystander cells alone, significant increases in expression of MAPK target genes were observed for MMC- and radiation-induced bystander effects but not for PHL. PHL is an acknowledged radiomimetic agent; however, in the present study, PHL responses did not resemble those of radiation. These results provide evidence for bystander-induced changes in MAPK proteins and downstream targets and suggest that the bystander effects are a part of a general stress response.