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 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 ␤-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 seleniuminduced 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 seleniuminduced 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.

Selenium Compounds Activate ATM-dependent DNA Damage Response via the Mismatch Repair Protein hMLH1 in Colorectal Cancer Cells*

“…S2). Consistent with the notion that selenium compounds can induce ROS formation (22,32), addition of the antioxidant NAC and Tempo dramatically suppressed the selenium-induced cell death in HCT 116ϩhMLH1 (Fig. 1, D-F) and HCT 116 cells (supplemental Fig.…”

“…1C) by colony formation assays. We chose the selenium compounds because the organic MSeA and MSeC are known to be very efficacious in suppressing tumors in animal models (31), yet Na 2 SeO 3 is as effective as the organic selenium compounds in activating early barriers of tumorigenesis in cell models (22). Here, we found that HCT 116ϩhMLH1 cells were significantly (p Ͻ 0.05) more sensitive than HCT 116 cells to the three selenium compounds in a dose-dependent manner.…”

“…Moreover, a linkage between hMLH1 and ATM after DNA damage has been demonstrated (20,21). We have shown recently that selenium compounds at doses Յ LD 50 can activate DNA damage response through ATM and ROS in noncancerous but not in cancerous cells (22). In the current study, we hypothesized that lack of a G 2 /M checkpoint response renders the hMLH1-deficient HCT 116 cells resistant to selenium-induced DNA damage response.…”

“…Immunofluorescence-Immunofluorescence analysis was performed as described previously (22). Briefly, HCT 116 and HCT 116ϩhMLH1 cells were grown on coverslips and incubated with selenium compounds for 0 -24 h. Alternatively, cells were pretreated with Noc (300 ng/ml) to capture cells in the G 2 /M phase.…”

Epilepsy: Selenium and Aging

“…Recently, the gene of Secisbp2 protein, which is related with synthesis of selenoproteins (Copeland and Driscoll 1999;Copeland, Fletcher et al 2000;Low, Grundner-Culemann et al 2000;Tujebajeva, Copeland et al 2000;Berry, Tujebajeva et al 2001;Copeland and Driscoll 2001;Copeland, Stepanik et al 2001;Fletcher, Copeland et al 2001;Copeland and Driscoll 2002;Lescure, Allmang et al 2002;Lescure, Fagegaltier et al 2002), has been studied as a possible target for hereditary diseases, an example of which includes human thyroid hormone metabolism disorder (Dumitrescu, Liao et al 2005). Selenium is also known as an important chemoprevention agent (El-Sayed, Aboul-Fadl et al 2006;Micke, Schomburg et al 2009) by inducing apoptosis in cancer cells (Jackson and Combs 2008) and senescence in the early stage of tumorigenesis (Wu, Kang et al 2010) in a dose-dependent manner. More than 50 years ago, the ROS (reactive oxygen species) theory of aging was proposed.…”