Selenium Compounds Activate Early Barriers of Tumorigenesis

Mandy M. Kang,Wen-Hsing Cheng,Norberta W. Schoene,Min Wu

doi:10.1074/jbc.m109.088781

Mandy M. Kang, Wen-Hsing Cheng + Show 2 more

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https://doi.org/10.1074/jbc.m109.088781

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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 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.

Highlights

Genome instability is a hallmark of carcinogenesis
The results suggest a novel role of selenium in the activation of early tumorigenesis barriers specific in non-cancerous cells, whereby selenium induces an ataxia telangiectasia mutated (ATM)-dependent senescence response that depends on reactive oxygen species
Selenium Treatment Results in ATM Ser-1981 Phosphorylation and ␥H2AX Formation in Non-cancerous Cells—ATM activation and DNA damage response occur in senescent cells at an early stage of tumorigenesis [1,2,3, 18]

Summary

Introduction

Genome instability is a hallmark of carcinogenesis. Recent advances suggest that major barriers of human tumorigenesis at the early stage include DNA damage response and senescence [1,2,3], both of which involve ATM activation. Previous studies have focused on selenium-induced stress responses in various cultured cancer cells, from which it is suggested that much of the role of selenium in cancer prevention is attributable to ROS-induced apoptosis or cell cycle arrest in cancer cells [11,12,13]. Consistent with this notion, it has been shown that selenium-induced apoptosis in cancer cells can be suppressed by antioxidants [14] and is p53-dependent [15]. It is known that selenium-induced oxidative stress or DNA damage can APRIL 16, 2010 VOLUME 285 NUMBER 16

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