Abstract |
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 2d, followed by recovery for up to 7d. 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.
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Authors | Wen-Hsing Cheng, Ryan T Y Wu, Min Wu, Caroline R B Rocourt, Jose A Carrillo, Jiuzhou Song, Christina T Bohr, Tiffany J Tzeng |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 420
Issue 1
Pg. 24-8
(Mar 30 2012)
ISSN: 1090-2104 [Electronic] United States |
PMID | 22390926
(Publication Type: Journal Article)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
- Cell Cycle Proteins
- DNA-Binding Proteins
- H2AX protein, human
- Histones
- Morpholines
- Organoselenium Compounds
- Pyrones
- Tumor Suppressor Proteins
- methylselenic acid
- ATM protein, human
- Ataxia Telangiectasia Mutated Proteins
- Atm protein, mouse
- Protein Serine-Threonine Kinases
- Exodeoxyribonucleases
- RecQ Helicases
- WRN protein, human
- Werner Syndrome Helicase
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Topics |
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
(antagonists & inhibitors)
- Cell Line, Tumor
- DNA Damage
- DNA-Binding Proteins
(antagonists & inhibitors)
- Drug Resistance, Neoplasm
(genetics)
- Exodeoxyribonucleases
(genetics, metabolism)
- Gene Knockdown Techniques
- Histones
(metabolism)
- Humans
- Mice
- Morpholines
(pharmacology)
- Necrosis
- Organoselenium Compounds
(pharmacology)
- Osteosarcoma
(metabolism, pathology)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Pyrones
(pharmacology)
- RecQ Helicases
(genetics, metabolism)
- Tumor Suppressor Proteins
(antagonists & inhibitors)
- Werner Syndrome Helicase
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