Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
Biochem Biophys Res Commun. 2012 Mar 30;420(1):24-8. doi: 10.1016/j.bbrc.2012.02.104. Epub 2012 Feb 27.
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.
WRN 蛋白（基因组的守护者）突变会导致 Werner 综合征，其特征为早衰表型和癌症易感性。甲基硒酸（MSeA）可激活 DNA 损伤反应，是一种优于抑制癌症小鼠模型中肿瘤发生的化合物。为了验证靶向 WRN 可以增强癌症细胞中硒毒性的假设，用 MSeA 处理同基因 WRN 短发夹 RNA（shRNA）和对照 shRNA U-2 OS 骨肉瘤细胞 2d，随后恢复至多 7d。WRN 缺失使 U-2 OS 细胞对 MSeA 诱导的坏死性死亡敏感。用共济失调毛细血管扩张突变（ATM）激酶抑制剂 KU55933 共同处理对照 shRNA 细胞，但不是 WRN shRNA 细胞，使它们对 MSeA 处理不敏感。WRN 不影响 MSeA 诱导的 ATM 在 Ser-1981 上的磷酸化或 H2A.X 在 Ser-139 上的磷酸化，但促进了从 MSeA 诱导的 DNA 损伤中恢复。总之，WRN 保护 U-2 OS 骨肉瘤细胞免受 MSeA 诱导的细胞毒性，表明氧化 DNA 修复途径是提高硒对肿瘤抑制功效的有前途的靶标。
