Arsenite induces premature senescence via p53/p21 pathway as a result of DNA damage in human malignant glioblastoma cells.
In this study, we investigate whether arsenite-induced DNA damage leads to p53-dependent premature senescence using human glioblastoma cells with p53-wild type (U87MG-neo) and p53 deficient (U87MG-E6). A dose dependent relationship between arsenite and reduced cell growth is demonstrated, as well as induced γH2AX foci formation in both U87MG-neo and U87MG-E6 cells at low concentrations of arsenite. Senescence was induced by arsenite with senescence-associated β-galactosidase staining. Dimethyl- and trimethyl-lysine 9 of histone H3 (H3DMK9 and H3TMK9) foci formation was accompanied by p21 accumulation only in U87MG-neo but not in U87MG-E6 cells. This suggests that arsenite induces premature senescence as a result of DNA damage with heterochromatin forming through a p53/p21 dependent pathway. p21 and p53 siRNA consistently decreased H3TMK9 foci formation in U87M G-neo but not in U87MG-E6 cells after arsenite treatment. Taken together, arsenite reduces cell growth independently of p53 and induces premature senescence via p53/p21-dependent pathway following DNA damage.
Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Yasuharu
Y
Ninomiya
Medical Physics Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Xing
X
Cui
Radiation Emergency Medicine Research Program, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Takeshi
T
Yasuda
Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Bing
B
Wang
School of Radiological Medicine and Protection, Medical College of Soochow University, 199 Ren Ai Rd, Suzhou Industrial Park, Suzhou 215123, China.
Dong
D
Yu
Research Program for Application of Heavy ions and Medical Science, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Emiko
E
Sekine-Suzuki
Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Mitsuru
M
Nenoi
D018053:Arsenites / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D018053:Arsenites; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D016159:Tumor Suppressor Protein p53; D008239:Lysine; C015001:arsenite