title: Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death.
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.
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA. whcheng@umd.edu
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Cheng
authors.forename: Ryan T Y
authors.initials: RT
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Caroline R B
authors.initials: CR
authors.lastname: Rocourt
authors.forename: Jose A
authors.initials: JA
authors.lastname: Carrillo
authors.forename: Jiuzhou
authors.initials: J
authors.lastname: Song
authors.forename: Christina T
authors.initials: CT
authors.lastname: Bohr
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Tzeng
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009336:Necrosis; D016566:Organoselenium Compounds / Q000494:pharmacology*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011753:Pyrones / Q000494:pharmacology; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors; D000071657:Werner Syndrome Helicase
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D016566:Organoselenium Compounds; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C008493:methylselenic acid; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase