Selenium induced DNA repair and cancer prevention.

A72

Several clinical trials are seeking to determine the efficacy of selenium in cancer prevention. There is evidence that selenium supplementation can reduce the incidence of a variety of human cancer types including lung, prostate, gastric, and esophageal. There are also studies in rats and mice that reveal selenium prevention of chemically-induced mammary and colon cancers. However, the mechanism by which selenium exerts its preventive effect remains to be identified. We have shown that different types of selenium exert different biochemical effects on the tumor suppressor p53, and we propose that these differential effects contribute to the mechanism of selenium prevention. Specifically, we have shown that methylseleninic acid induces p53 serine phosphorylation, which is associated with apoptosis. Selenomethionine, on the other hand, caused no detectable serine phosphorylation. Selenomethionine treated cells have an altered redox environment that leads to a reduction of p53 cysteine residues. The reduced conformation of p53 induces DNA binding and transcription of DNA damage recognition proteins. The damage recognition proteins XPC and p48XPE comprise the rate-limiting step in the nucleotide excision repair process. In this study, we analyzed the expression of several DNA damage recognition factors in wildtype and p53-null mouse embryo fibroblasts following treatment with selenomethionine. Selenomethionine treatment had no effect on p53-null cells, but in wildtype cells, there was increased expression of rate-limiting damage recognition factors, which coincided with an increase in the rate of repair of ultraviolet radiation-induced lesions. We also show that selenomethionine elevates DNA repair in primary mouse bone marrow and rat gut epithelial cells. The preventive effect of selenium may depend on the relative contribution of particular selenium compounds and their differential effects of either apoptosis or DNA repair.