Mitochondrial reactive oxygen species perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of PP2A in lowdose irradiated human fibroblasts

• Published in: Oncotarget Vol. 7; no. 3; pp. 3559 - 3570
• Main Authors: Shimura, Tsutomu, Sasatani, Megumi, Kamiya, Kenji, Kawai, Hidehiko, Inaba, Yohei, Kunugita, Naoki
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19.01.2016
• Subjects: Adenosine Triphosphate - metabolism; Antioxidants - pharmacology; Apoptosis - drug effects; Apoptosis - radiation effects; Blotting, Western; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Cells, Cultured; Cyclin D1 - metabolism; DNA Damage - radiation effects; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - radiation effects; Gamma Rays; Humans; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung - radiation effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - radiation effects; Oxidation-Reduction; Protein Phosphatase 2 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Radiation Dosage; Reactive Oxygen Species - metabolism; Research Paper; low-dose radiation; AKT; cyclin D1; mitochondria; ROS
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6518

Here we investigated the cellular response of normal human fibroblasts to repeated exposure to low-dose radiation. In contrast to acute single radiation, low-dose fractionated radiation (FR) with 0.01 Gy/fraction or 0.05 Gy/fraction for 31 days increased in mitochondrial mass, decreased cellular levels of the antioxidant glutathione and caused persistent accumulation of mitochondrial reactive oxygen species (ROS). Excess ROS promoted oxidative inactivation of protein phosphatase PP2A which in turn led to disruption of normal negative feed-back control of AKT/cyclin D1 signaling in cells treated with long-term FR. The resulting abnormal nuclear accumulation of cyclin D1 causes growth retardation, cellular senescence and genome instability in low-dose irradiated cells. Thus, loss of redox control and subsequently elevated levels of ROS perturb signal transduction as a result of oxidative stress. Our study highlights a specific role of mitochondrial ROS in perturbation of AKT/cyclin D1 cell cycle signaling after low-dose long-term FR. The antioxidants N-acetyl-L-cysteine, TEMPO and mitochondrial-targeted antioxidant Mito-TEMPO provided protection against the harmful cell cycle perturbations induced by low-dose long-term FR.