Mechanism of radiation-induced bystander effect: Role of the cyclooxygenase-2 signaling pathway

Abstract

The radiation-induced bystander effect is defined as ''the induction of biological effects in cells that are not directly traversed by a charged particle but are in close proximity to cells that are.'' Although these bystander effects have been demonstrated with a variety of biological endpoints in both human and rodent cell lines (as well as in 3D tissue samples), the mechanism of the phenomenon is not known. Although gap junction communication and the presence of soluble mediator(s) are both known to play important roles in the bystander response, the precise signaling molecules have yet to be identified. By using the Columbia University charged particle beam in conjunction with a strip dish design, we show here that the cyclooxygenase-2 (COX-2, also known as prostaglandin endoperoxide synthase-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. Because the critical event of the COX-2 signaling is the activation of the mitogen-activated protein kinase pathways, our finding that inhibition of the extracellular signal-related kinase phosphorylation suppressed bystander response further confirmed the important role of mitogen-activated protein kinase signaling cascade in the bystander process. These results provide evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory response, is the critical signaling link for the bystander phenomenon.

TNF-TNFR2/p75 Signaling Inhibits Early and Increases Delayed Nontargeted Effects in Bone Marrow-derived Endothelial Progenitor Cells

“…Many of these cytokines, chemokines, and inflammatory enzymes (e.g. COX-2) are implicated in mediating RBR in variety of cells (38). However, the role of TNF receptors, p55 or p75, in regulating RBR in endothelial lineage cells, specifically in EPCs, is largely unknown.…”

Radiation-induced bystander effects

“…This effect is believed to involve signaling via the cell membrane since treatment of cells with lindane, or other agents that inhibits gap junction intercellular communication, reduced the stress response in the bystander cells. Adding to the complexity of bystander response, recent results provide evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory response, is a critical signaling link for the bystander phenomenon [8].…”

The Yin and Yang of Low-Dose Radiobiology

“…It is known that insulin growth factor activates the mitogen-activated protein kinase (MAPK) signaling cascade, and activation of extracellular signal-related kinase (ERK) by phosphorylation is a critical upstream event preceding COX-2 expression. Using Western blot analyses, it was evident that a strong upregulation of phospho-ERK levels in both α-irradiated and bystander normal human fi broblasts occurred 4 h after irradiation [21]. In fact, increased levels of phospho-ERK could even be detected 16 h after treatment, indicating a persistent response to the bystander signaling.…”

“…If activation of the MAPK signaling cascade and ERK phosphorylation are essential in mediating the bystander effect, it should be possible to mitigate the later response by using a specifi c inhibitor of the MEK-ERK signaling cascade. In fact, pretreatment of cells with a noncytotoxic dose of PD 98059 (50 μM), a specifi c inhibitor of MEK-ERK kinase, completely suppressed bystander toxicity observed in the human fi broblast cultures [21]. The role of MAPK/ERK pathways in radiation-induced adaptive response was previously demonstrated in mammalian cells.…”

“…Previous studies have shown that cyclooxygenase 2 (COX-2) is an important signaling molecule for radiation-induced bystander effects [21]. It is known that insulin growth factor activates the mitogen-activated protein kinase (MAPK) signaling cascade, and activation of extracellular signal-related kinase (ERK) by phosphorylation is a critical upstream event preceding COX-2 expression.…”