Selenoproteins in Cancer Etiology

Selenium exerts its functions mainly through its incorporation into selenoproteins, which contain the amino acid selenocysteine. Animal and epidemiological, but not supplementation studies, have provided evidence supporting the role of selenium in cancer etiology. Selenoproteins GPx-1 and Sep15, specifically the polymorphisms in their genes, have been implicated in mediating the chemopreventative effect of selenium in several cancer types. Polymorphisms in MnSOD confer different risk for prostate cancer and poor outcome depending on dietary antioxidant intake and the activity of GPx-1. The gene-gene interaction between MnSOD and GPx-1 was examined to elucidate the molecular mechanisms underlying the differing levels of cancer risk. In order to investigate whether a molecular interaction between polymorphic variants of GPx-1 and MnSOD exists, GPx-1 and MnSOD genotype and levels were manipulated in MCF-7 cells to exclusively express allele specific variants of the anti-oxidant enzymes by transfection. Allele-specific interactions of GPx-1 and MnSOD altered the levels of critical proteins implicated in cancer. Despite these interactions, GPx-1 and MnSOD levels were not associated with prostate cancer recurrence after radical prostatectomy. An association between polymorphisms in Sep15, selenium levels and prostate cancer mortality has been reported. The functional polymorphisms, which are 6-fold more prevalent in African Americans, form a haplotype and exhibit a trend toward an association with prostate cancer mortality. In order to determine whether the levels of Sep15 are associated with prostate cancer tumor grade, tissue samples from a cohort of men who underwent radical prostatectomy were examined. Although Sep15 levels were not associated with prostate tumor grade, its levels were reduced in prostate cancers compared to benign tissues, as well as in prostate tumors of African Americans compared to Caucasians. The studies indicate the importance of subcellular localization of selenoproteins in different locations than traditionally observed, and suggest that the localization of GPx-1 and Sep15 may be important in elucidating their roles in carcinogenesis.