Selenium compounds activate early barriers of tumorigenesis

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 and methylselenocysteine for 48 hours, followed by a recovery of 1–7 days. Here we show that doses of the selenium compounds ≤LD50 can induce cellular senescence, as evidenced by the expression of senescence‐associated β‐galactosidase and 5‐bromo‐2‐deoxyuridine incorporation, in normal but not cancerous cells. In response to clastogens, 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 non‐cancerous cells, whereby selenium induces an ATM‐dependent senescence response that depends on reactive oxygen species.Grant Funding Source: University of maryland