title: Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway.
abstract: Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of ATO on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive.
authors: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chingshouhu@gmail.com
authors: Yu-Chen
authors: YC
authors: Hu
authors: Bau-Shan
authors: BS
authors: Hsieh
authors: Hsiao-Ling
authors: HL
authors: Cheng
authors: Li-Wen
authors: LW
authors: Huang
authors: Tzu-Ching
authors: TC
authors: Huang
authors: I-Yu
authors: IY
authors: Huang
authors: Kee-Lung
authors: KL
authors: Chang
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010087:Oxides / Q000633:toxicity*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D001152:Arsenicals; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010087:Oxides; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D000077237:Arsenic Trioxide