Growth arrest in G1 protects against oxygen-induced DNA damage and cell death.
Although oxygen is required for normal aerobic respiration, hyperoxia (95% O(2)/5% CO(2)) damages DNA, inhibits proliferation in G1, S and G2 phases of the cell cycle, and induces necrosis. The current study examines whether growth arrest in G1 protects pulmonary epithelial cells from oxidative DNA damage and cell death. Mv1Lu pulmonary adenocarcinoma cells were chosen for studies because hyperoxia inhibits their proliferation in S and G2 phase, while they can be induced to arrest in G1 by altering culture conditions. Hyperoxia inhibited proliferation, increased intracellular redox, and rapidly reduced clonogenic survival. In contrast, Mv1Lu cells treated with transforming growth factor (TGF)-beta1, deprived of serum or grown to confluency, arrested and remained predominantly in G1 even during exposure. Growth arrest in G1 significantly enhanced clonogenic survival by 10-50-fold. Enhanced survival was not due to reduction in the intracellular redox-state of the cells, but instead was associated with reduced DNA strand breaks and p53 expression. Our findings suggest that the protective effects of G1 is mediated not simply by a reduction in intracellular ROS, but rather through an enhanced ability to limit or rapidly recognize and repair damaged DNA.
Rancourt
Raymond C
RC
Department of Environmental Medicine, The University of Rochester, Rochester, New York 14642, USA.
Hayes
Daniel D
DD
Chess
Patricia R
PR
Keng
Peter C
PC
O'Reilly
Michael A
MA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008907:Mink; D010084:Oxidation-Reduction; D010100:Oxygen / Q000633:toxicity*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016895:Culture Media, Serum-Free; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D010100:Oxygen