Glutathione peroxidase-1 expression enhances recovery of human breast carcinoma cells from hyperoxic cell cycle arrest.

We previously reported that hyperoxia (95% O(2)) induces an S-phase cell cycle arrest in glutathione peroxidase-deficient human carcinoma cells T47D-H3 (Exp. Cell Res. 256:347-357; 2000). Here, we investigated whether increasing the peroxide scavenging capacity via glutathione peroxidase-1 (GPx1) expression can prevent cell cycle alterations induced by oxidative stress. We show that GPx1-proficient T47D-GPx-2 transfectant cells, in which GPx1 concentration is most elevated in mitochondria (Biochem. Biophys. Res. Commun. 272:416-422; 2000), are partially resistant to cell cycle inhibition induced by hyperoxia or menadione exposure. Transient cell growth resistance was observed at the level of cell cycle phase distribution, Cdk2 activity, and DNA synthesis after 40 h hyperoxia. This differential resistance was associated with an inhibition of ROS production and lipid peroxidation induced by hyperoxia. After 64 h hyperoxic exposure, cell growth was completely abolished in both cell lines, despite elevated glutathione levels. However, in contrast to the GPx1-deficient cells, T47D-GPx-2 cells showed an increased capacity to recover from a cell cycle arrest mediated by a 64 h hyperoxic stress. Differential recovery was also observed at the ultrastructural level between Gpx1-proficient and -deficient cells. These data indicate that GPx1 played an important role in the cell capacity to recover from hyperoxic insults. The limited protection conferred by GPx1 during hyperoxia suggests that the deleterious effects were partially mediated by peroxide-derived free radicals, but also involved the action of nonperoxide-derived reactive species.