Effect of selenoproteins and DNA mismatch repair in colorectal cancer cells treated with methylseleninic acid

A significant portion of colorectal cancer is characterized by genome instability due to a defective mismatch repair (MMR) system, which senses DNA damage after DNA replication and provokes repair, checkpoint and apoptotic responses. The majority of colorectal cancers exhibit loss‐of‐function mutations in the APC and/or p53 gene in the early stage of tumorigenesis, turning normal cells to adenoma. Our recent report indicates that toxic doses of selenium target the MMR pathway and sensitize the cancerous HCT 116 colorectal cells to apoptosis because the lack of hMLH1 renders the cancerous cells escape from the selenium‐induced, ATM‐mediated G2/M checkpoint and cell death [Qi et al. 2010, J Biol. Chem., 285, 33010‐33017]. Here we study the role of selenoproteins and DNA‐PK cs , a functional homolog of the ATM kinase, as well as the APC and p53 tumor suppressors, in the response of colorectal cancer cells to selenium compounds. We found that GPX1 protein level increases in HCT 116 cells treated with 0–2 μM of methylseleninic acid (MSeA), and the extent of which is greater in HCT 116+hMLH1 cells than in HCT 116 cells. Pretreatment of the cells with NU 7026, a DNA‐PK cs kinase inhibitor, prevented MSeA‐induced G2/M blockage and the association between hMLH1 and hPMS2 proteins, a heterodimer critical for functional MMR. Taken together, in addition to selenium metabolites, selenoproteins may also play a role in the selenium chemoprevention of colorectal carcinogenesis in a manner dependent on the ATM‐ and DNA‐PK cs ‐regulated DNA damage response. Grant Funding Source : UMCP