Selenium compounds activate early barriers of tumorigenesis.
Selenium chemoprevention by apoptosis has been well studied, but it is not clear whether selenium can activate early barriers of tumorigenesis, namely senescence and DNA damage response. To test this hypothesis, we treated normal and cancerous cells with a gradient concentration of sodium selenite, methylseleninic acid and methylselenocysteine for 48 h, followed by a recovery of 1-7 days. Here we show that selenium compounds at doses of </=LD(50) can induce cellular senescence, as evidenced by the expression of senescence-associated beta-galactosidase and 5-bromo-2-deoxyuridine incorporation, in normal but not cancerous cells. In response to clastogens, the ataxia telangiectasia mutated (ATM) protein is rapidly activated, which in turn initiates a cascade of DNA damage response. We found that the ATM pathway is activated by the selenium compounds, and the kinase activity is required for the selenium-induced senescence response. Pretreatment of the MRC-5 non-cancerous cells with the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl suppresses the selenium-induced ATM activation and senescence. Taken together, the results suggest a novel role of selenium in the activation of early tumorigenesis barriers specific in non-cancerous cells, whereby selenium induces an ATM-dependent senescence response that depends on reactive oxygen species.
Wu
Min
M
Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742, USA.
Kang
Mandy M
MM
Schoene
Norberta W
NW
Cheng
Wen-Hsing
WH
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000517:prevention & control; D016566:Organoselenium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018036:Selenium Compounds / Q000494:pharmacology*; D017279:Selenocysteine / Q000031:analogs & derivatives; D018038:Sodium Selenite / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D025521:Tumor Suppressor Proteins; D017279:Selenocysteine; C008493:methylselenic acid; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D018038:Sodium Selenite; D003545:Cysteine; C002979:selenomethylselenocysteine