Induction of Cellular Senescence and DNA Damage Response by Sodium Selenite

Abstract

Cells respond to DNA damage by induction of apoptosis, DNA damage checkpoint, and senescence, all of which have been proposed as barriers of tumorigenesis. Although selenium chemoprevention by apoptosis has been well studied, it is not clear whether and how other tumorigenesis barriers participate in selenium chemoprevention. To address these issues, we treated MRC-5 normal lung fibroblasts with 0–5 μM sodium selenite in a series of time course studies. We employed a number of senescence markers, including the measurement of senescence-associated expression of β-galactosidase (SA-β-gal). At day 7, there are clear features of stress-induced senescence as evidenced by SA-β-gal staining in cells treated with selenite at 1 and 2 μM. At a concentration of 5 μM, a significant portion of cells die. In response to clastogens, ATM is rapidly activated, which in turn initiates a cascade of DNA damage response including histone H2AX phosphorylation at Ser-139 (also known as γH2AX). By using antibodies against the phosphorylated form of the proteins, the results showed that there is a selenium dose-dependent increase in the level of γH2AX at 3 h and 6 h. Taken together, the results suggest a novel mechanism of selenium chemoprevention by which selenium induces DNA damage response and senescence to inhibit cancer cell proliferation.