Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect

Radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the final biological consequences of exposure to low doses of radiation. Evidence suggests that targeted cytoplasmic irradiation results in mutation in the nucleus of the "hit" cells and that cells, which are not directly hit by an alpha particle, whether nuclear or cytoplasm, but are in the vicinity of one that does get hit, contribute to the genotoxic response of the cell population. Although radiation-induced bystander effects have been well documented in a variety of biological systems, the mechanism is not known. Using the Columbia University charged particle beam in conjunction with a novel strip dish design, we showed recently that the cyclooxygenase-2 (COX-2) signaling cascade plays an essential role in the bystander process. Treatment of bystander cells with NS-398, which suppresses COX-2 activity, significantly reduced the bystander effect as well as the induction of the mitogen-activated protein kinase (MAPK) pathways. These results provided the first evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory responses, is the critical signaling link for the bystander phenomenon. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon together with evidence of their occurrence in vivo will allow us to formulate a more accurate model in assessing the health effects of low doses of ionizing radiation.