|Wu, Min -|
|Kang, Mandy -|
|Cheng, Wen-Hsing -|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 15, 2010
Publication Date: February 15, 2010
Citation: Wu, M., Kang, M., Schoene, N.W., Cheng, W. 2010. Selenium compounds activate early barriers of tumorigenesis. Journal of Biological Chemistry. 285(16):12055-12062. Interpretive Summary: Selenium (Se) is an dietary essential nutrient that is thought to have chemo-preventive properties. Both epidemiological studies and clinical trials have produced conflicting results about beneficial effects of supplementing with supra-amounts of Se on the development of cancer. Thus, there is an urgent need to investigate how Se acts within cells to prevent their transformation into tumors. We report on our studies where both normal and cancer cells were supplemented with several different forms of Se. Our results demonstrated that normal cells become senescent (growth stoppage) upon treatment with the Se compounds while the tumor cells did not. Cellular senescence in the normal cells is an indication of a delay or prevention of tumorigenesis. We conclude that this finding suggests a novel mechanism to explain how Se may act as a barrier to the development of tumors. This new information about the actions of Se advances the understanding of the role of this essential nutrient in preventing cancer and will be of interest to researchers in nutrition, oncology, and other health-related fields.
Technical Abstract: 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 address this issue, we treated normal and cancerous cells with a gradient concentration of sodium selenite, methylseleninic acid (MSeA) and methylselenocysteine (MSeC) for 48 hours, followed by a recovery of 1-7 days. Here we show that sub-lethal doses of the selenium compounds 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, ataxia telangiectasia mutated (ATM) 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. Pre-treatment of the MRC-5 cells with an antioxidant, N-acetyl cysteine, prevents the Se-induced ATM activation and senescence. Taken together, the results suggest a novel role of selenium in the activation of tumorigenesis barriers specific in precancerous cells, whereby selenium induces an ATM-dependent senescence response that depends on reactive oxygen species (ROS).