Induction of Cellular Senescence and DNA Damage Response by Sodium Selenite

Abstract

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 this issue, we treated MRC‐5 normal lung fibroblasts with 0‐10 µM sodium selenite, 0‐10 µM methylseleninic acid (MSeA) and 0‐500 µM methylselenocysteine (MSeC) for 48 hours, followed by a recovery of 1‐7 days. There is a selenium dose‐dependent decline in cell survival during the time course. To determine whether senescence response can be induced by sub‐lethal doses of the selenium compounds, we measured senescence‐associated expression of â‐galactosidase (SA‐â ‐gal) and bromodeoxyuridine (5‐bromo‐2‐deoxyuridine, BrdU) incorporation. We observed increased SA‐â ‐gal staining and decreased incorporation of BrdU into the replicative DNA after cellular exposure to the selenium compounds. 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 ãH2AX). Results from Western analysis demonstrated increased expression of phosphorylated‐ATM and ãH2AX after the selenium treatment. Taken together, the results suggest a novel mechanism of selenium chemoprevention by which selenium induces DNA damage response and senescence to inhibit tumorigenesis. Grant Funding Source N/A