piperidines and methylselenic-acid

Epidemiological and animal studies indicate that selenium supplementation suppresses risk of colorectal and other cancers. The majority of colorectal cancers are characterized by a defective DNA mismatch repair (MMR). Here, we have employed the MMR-deficient HCT 116 colorectal cancer cells and the MMR-proficient HCT 116 cells with hMLH1 complementation to investigate the role of hMLH1 in selenium-induced DNA damage response, a tumorigenesis barrier. The ATM (ataxia telangiectasia mutated) protein responds to clastogens and initiates DNA damage response. We show that hMLH1 complementation sensitizes HCT 116 cells to methylseleninic acid, methylselenocysteine, and sodium selenite via reactive oxygen species and facilitates the selenium-induced oxidative 8-oxoguanine damage, DNA breaks, G(2)/M checkpoint response, and ATM pathway activation. Pretreatment of the hMLH1-complemented HCT 116 cells with the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl or the ATM kinase inhibitor KU55933 suppresses hMLH1-dependent DNA damage response to selenium exposure. Selenium treatment stimulates the association between hMLH1 and hPMS2 proteins, a heterodimer critical for functional MMR, in a manner dependent on ATM and reactive oxygen species. Taken together, the results suggest a new role of selenium in mitigating tumorigenesis by targeting the MMR pathway, whereby the lack of hMLH1 renders the HCT 116 colorectal cancer cells resistant to selenium-induced DNA damage response.

Topics: Acetylcysteine; Adaptor Proteins, Signal Transducing; Adenosine Triphosphatases; Anticarcinogenic Agents; Antioxidants; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Tumor; Colorectal Neoplasms; Cysteine; DNA Breaks; DNA Mismatch Repair; DNA Repair Enzymes; DNA-Binding Proteins; Drug Resistance, Neoplasm; Guanosine; Humans; Mismatch Repair Endonuclease PMS2; Morpholines; MutL Protein Homolog 1; Nuclear Proteins; Organoselenium Compounds; Piperidines; Protein Serine-Threonine Kinases; Pyrones; Reactive Oxygen Species; Selenocysteine; Sodium Selenite; Tumor Suppressor Proteins