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Targeting DNA repair protein as an approach for sensitizing cancer cells to methylseleninic acid
Author(s) -
Tzeng Tiffany J,
Wu Ryan TY,
Rocourt Caroline RB,
Cheng Wen-Hsing
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.253.4
Subject(s) - dna repair , dna damage , genome instability , dna , cancer research , microbiology and biotechnology , werner syndrome , cancer cell , biology , mutation , cancer , genetics , helicase , rna , gene
DNA‐dependent protein kinase (DNA‐PK cs ) is part of the DNA‐PK complex that senses and repairs DNA double strand breaks by the nonhomologous end‐joining pathway. The WRN protein is a member of the RecQ DNA helicases and plays essential roles in the maintenance of genome stability. Whereas mutations in WRN result in Werner syndrome that displays premature aging phenotypes and cancer predisposition, the only human PRKDC ( DNA‐PKcs ) mutation known to date is the L3062R missense mutation found in a severe combined immunodeficiency patient. To test the hypothesis that targeting DNA repair proteins can improve the cytotoxic effect of selenium in cancer cells, we tested the sensitivity of 1) WRN small hairpin RNA (shRNA) and scrambled shRNA U‐2 OS osteosarcoma cells and 2) DNA‐PK −/− and control HCT 116 colorectal cancer cells to methylseleninic acid (MSeA, 0–5 μM). Here we show that DNA‐PK cs or WRN deficiency sensitizes the cancerous cells to MSeA‐induced cytotoxicity in a dose‐dependent manner. DNA‐PK cs or WRN does not affect MSeA‐induced ATM phosphorylation on Ser‐1981 or H2A.X phosphorylation on Ser‐139. However, WRN promotes recovery of the cells from MSeA‐induced DNA damage. Taken together, DNA‐PK cs and WRN protect cancer cells against MSeA‐induced cytotoxicity, suggesting that targeting DNA repair pathway is a promising approach for improving selenium chemoprevention.