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
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
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 β-galactosidase and 5-bromo-2deoxyuridine 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 noncancerous cells with the antioxidant N-acetylcysteine or 2,2,6,6tetramethylpiperidine-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.The tumor suppressor p53 is a substrate of the ATM kinase and plays an important role in senescence. To determine mechanism by which selenium induces the ATMdependent senescence, we employed shRNA knockdown approach and other DNA damage assays to determine the role of p53 in the senescence response. Results from senescence-associated expression of β-galactosidase assay indicate that p53 shRNA MRC-5 cells did not show senescent phenotype with a series of concentrations of methylseleninic acid (0-10 μM) after 7-day recovery. However, loss of p53 renders MRC-5 cells more resistant to MSeA treatment and increased its genomic instability.We also observe that MSeA can cause increased irreversible G2/M arrest in scramble MRC-5 cells but treated p53 shRNA MRC-5 can recover back to non-treated status after 7-day recovery. Taken together, p53 is involved in the ATM-dependent senescence in the response of MRC-5 normal cells to selenium compounds. SELENIUM COMPOUNDS ACTIVATE EARLY BARRIERS OF TUMORIGENESIS
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.