Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death.

Mutations in the Werner syndrome protein (WRN), a caretaker of the genome, result in Werner syndrome, which is characterized by premature aging phenotypes and cancer predisposition. Methylseleninic acid (MSeA) can activate DNA damage responses and is a superior compound to suppress tumorigenesis in mouse models of cancer. To test the hypothesis that targeting WRN can potentiate selenium toxicity in cancer cells, isogenic WRN small hairpin RNA (shRNA) and control shRNA U-2 OS osteosarcoma cells were treated with MSeA for 2d, followed by recovery for up to 7d. WRN deficiency sensitized U-2 OS cells to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139, but promoted recovery from the MSeA-induced DNA damage. Taken together, WRN protects U-2 OS osteosarcoma cells against MSeA-induced cytotoxicity, suggesting that oxidative DNA repair pathway is a promising target for improving the efficacy of selenium on tumor suppression.

Selenium supranutrition: are the potential benefits of chemoprevention outweighed by the promotion of diabetes and insulin resistance?

Selenium was considered a toxin until 1957, when this mineral was shown to be essential in the prevention of necrotic liver damage in rats. The hypothesis of selenium chemoprevention is principally formulated by the observations that cancer incidence is inversely associated with selenium status. However, recent clinical and epidemiological studies demonstrate a role for some selenoproteins in exacerbating or promoting other disease states, specifically type 2 diabetes, although other data support a role of selenium in stimulating insulin sensitivity. Therefore, it is clear that our understanding in the role of selenium in glucose metabolism and chemoprevention is inadequate and incomplete. Research exploring the role of selenium in individual healthcare is of upmost importance and possibly will help explain how selenium is a double-edged sword in the pathologies of chronic diseases.

The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response.

Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.