Cells that are not hit by ionizing radiation but are close to cells that are hit can suffer radiation-induced damage. The effects of radiation on these "bystander cells" involve signals conveyed through gap junctions, soluble factors, or both, but the identity of the molecules mediating this response remains unclear. Zhou et al. exposed cultured human fibroblasts to α particles, such that cells growing on 38-μm-thick mylar strips were protected from radiation, whereas adjoining cells growing on 6-μm mylar sheets were not. Survival was decreased in bystander cells compared with control (nonirradiated) cells, and mutation of the HPRT– locus was increased, although neither of these effects was as great in bystander cells as in directly irradiated cells. cDNA microarray analysis combined with reverse transcription polymerase chain reaction (RT-PCR) and Western analysis revealed that the expression of COX-2 (which encodes cyclooxygenase-2) was increased in bystander cells compared with control cells, whereas that of IGFBP-3 (which encodes IGF-binding protein 3, which interferes with insulin-like growth factors binding to their cell surface receptors) was decreased. The COX-2 inhibitor NS-398 decreased mutation of HPRT– in bystander cells, as did application of exogenous IGFBP-3. Bystander cells showed enhanced phosphorylation of extracellular signal-regulated kinase (ERK), phosphorylation and activation of which takes place as part of the response to IGF and other cytokines and which has been implicated in stimulating COX-2 expression. Moreover, the survival of bystander cells was increased almost to that of control cells by pharmacological inhibition of ERK signaling. Thus, the authors propose that activation of COX-2 signaling by way of ERK plays a critical role in the bystander response.
H. Zhou, V. N. Ivanov, J. Gillespie, C. R. Geard, S. A. Amundson, D. J. Brenner, Z. Yu, H. B. Lieberman, T. K. Hei, Mechanism of radiation-induced bystander effect: Role of the cyclooxygenase-2 signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 102, 14641-14646 (2005). [Abstract] [Full Text]