Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death
| Autor: | Caroline Rocourt, Jiuzhou Song, Christina T. Bohr, Ryan T.Y. Wu, Min Wu, Wen-Hsing Cheng, Tiffany J. Tzeng, José A. Carrillo |
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| Rok vydání: | 2012 |
| Předmět: |
Premature aging
congenital hereditary and neonatal diseases and abnormalities Werner Syndrome Helicase DNA damage Morpholines Biophysics Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology medicine.disease_cause Biochemistry Histones Small hairpin RNA Mice Necrosis Cell Line Tumor Organoselenium Compounds medicine Animals Humans education Molecular Biology Werner syndrome Osteosarcoma education.field_of_study RecQ Helicases Kinase Tumor Suppressor Proteins nutritional and metabolic diseases Cell Biology medicine.disease Molecular biology DNA-Binding Proteins Exodeoxyribonucleases Drug Resistance Neoplasm Pyrones Gene Knockdown Techniques Cancer cell Carcinogenesis DNA Damage |
| Zdroj: | Biochemical and Biophysical Research Communications. 420:24-28 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2012.02.104 |
| Popis: | Mutations in the Werner syndrome protein (WRN), a caretaker of the genome, result in Werner syndrome, which is characterized by premature aging phenotypes and cancer predisposition. Methylseleninic acid (MSeA) can activate DNA damage responses and is a superior compound to suppress tumorigenesis in mouse models of cancer. To test the hypothesis that targeting WRN can potentiate selenium toxicity in cancer cells, isogenic WRN small hairpin RNA (shRNA) and control shRNA U-2 OS osteosarcoma cells were treated with MSeA for 2 d, followed by recovery for up to 7 d. WRN deficiency sensitized U-2 OS cells to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139, but promoted recovery from the MSeA-induced DNA damage. Taken together, WRN protects U-2 OS osteosarcoma cells against MSeA-induced cytotoxicity, suggesting that oxidative DNA repair pathway is a promising target for improving the efficacy of selenium on tumor suppression. |
| Databáze: | OpenAIRE |
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