Production of a signal by irradiated cells which leads to a response in unirradiated cells characteristic of initiation of apoptosis

Abstract

Summary This study investigated the ability of medium from irradiated cells to induce early events in the apoptotic cascade, such as mobilization of intracellular calcium, loss of mitochondrial membrane potential and increase in reactive oxygen species, in cells which were never exposed to radiation. Medium from irradiated human keratinocytes was harvested and transferred to unirradiated keratinocytes. Endpoints characteristic of the initiation of apoptosis were monitored for a period of 24 h following medium transfer. Clonogenic survival was also measured. Rapid calcium fluxes (within 30 s), loss of mitochondrial membrane potential, increases in reactive oxygen species (from 6 h after medium transfer), an increase in the number of apoptotic cells (48 hours after medium transfer) and a marked reduction in clonogenic survival (after 9 days) were observed. There was no significant difference between medium generated by cells irradiated at 0.5 Gy or 5 Gy. The data suggest that initiating events in the apoptotic cascade were induced in unexposed cells by a signal produced by irradiated cells.

Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation

“…Potentially related to the mechanisms mediating cytogenetic damage not requiring gap-junctional communication is the finding that the medium in which certain cells have been irradiated contains an activity, probably a protein, that produces cytotoxic effects in nonirradiated cells Lyng et al, 2000Lyng et al, , 2002Mothersill et al, 2000bMothersill et al, , 2001Seymour and Mothersill, 2000). The first detectable effect of the medium containing the cytotoxic activity on recipient cells is a rapid (1-2 min) calcium pulse followed 30 min-2 h later by changes in mitochondrial membrane permeability and the induction of ROS (Lyng et al, 2000(Lyng et al, , 2002; a role for mitochondrial metabolism is suggested by the lack of signal production by cells that lacked functional glucose-6-phosphate dehydrogenase (Mothersill et al, 2000b).…”

Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

“…These bystander-like interactions could involve the production of cytokines (Iyer and Lehnert, 2000) and/or free radical production (Lyng et al, 2000). Increased levels of reactive oxygen species in genomically unstable clones have been described (Clutton et al, 1996;Limoli et al, 1998Limoli et al, , 2001, and recently it was reported that X radiation caused a persistent induction of reactive oxygen species in normal human fibroblasts (Rugo et al, 2002).…”

The Bystander Effect: Recent Developments and Implications for Understanding the Dose Response

“…Those data clearly show that the protective effect was lost and transformation increased above control at doses between 100 and 300 mGy. Both protective bystander effects (Azzam et al, 1996;Broome et al, 2002) and detrimental bystander effects (Lyng et al, 2000;Seymour and Mothersill, 2000) have been shown to result from γ -radiation exposure at doses between 1 and 500 mGy. The data in Figure 2 therefore suggest the existence of a transition dose point between 100 and 300 mGy, below which protective effects, including protective bystander effects, predominate, and above which detrimental effects overwhelm the protective effects.…”