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Opinion

Diet, nutrition, and cancer

YOUR DOSE OF MEDICINE - Charles C. Chante MD -
Selenium
One of the most promising candidate chemopreventive agents is the essential trace element selenium. Decades of animal studies have consistently demonstrated that supplementing the diet of rodents with low, nontoxic amounts of selenium is effective in reducing cancer incidence in response to a broad range of carcinogens in most organ systems examined. In humans, several groups reported an inverse correlation between dietary intake of selenium and cancer incidence at several sites, including lung, colon, and prostate. Human supplementation studies have been few, but the reduction in cancer incidence as a consequence of consuming selenium as a supplement at levels obtainable from over-the-counter products indicated that selenium was effective in reducing cancer incidence in lung, colon, prostate, and liver. Because of this accumulative body of evidence, large chemopreventive human studies have been initiated. However, the mechanism by which selenium may reduce cancer remains unknown.

It is likely that many of the effects of selenium are mediated through its role as a constituent of selenium-containing proteins. Twenty-five selenoprotein were discovered in the human genome (24 in the mouse) and all contain selenium as the amino acid selenocysteine. Sec is incorporated cotranslationally during synthesis in response to in-frame UGA codons in the mRNA for these selenoproteins. Sec insertion requires dedicated translation factors including a SectRNA and elongation factor in addition to the RNA element in the 3-untranslated portion of the mRNA that directs Sec incorporation in response to all in-frame UGA CODONS (12-13). In mammalian cells, this process is highly regulated and responsive to selenium availability, both at the levels of RNA stability and translation. Whether individual selenoproteins or selenoproteins as a group are involved in the health benefits associated with selenium remains unknown.

Selenium is an essential micronutrient shown to reduce colon cancer incidence and preneoplastic aberrant crypts foci in animal models. In human studies, data have indicated that selenium levels are inversely associated with cancer mortality and incidence. A prospective case-control study indicated a statistically significant inverse association between toenail selenium levels and the risk of colon cancer. A significant inverse association between selenium levels and the incidence of large adenomatous polyps, after adjustment for confounding variables in patients <60 years of age (odds ration (OR) = 0.17, P=0.029), was also reported. The association between selenium intake and colon cancer risk was recently substantiated by an analysis of pooled data from 3 independent studies. In human supplementation trials, selenium reduced cancer mortality and colorectal cancer incidence, although the statistical significance decreased with longer follow-up.

One mechanism by which selenium may influence cancer incidence is via its effects on selenium-containing proteins. One selenoprotein, cytoplasmic glutathione proxidase (GPX1), is an intracellular selenium-dependent enzyme that is ubiquitously expressed and detoxifies hydrogen and lipid peroxides. GPIX1 levels are particularly responsive to fluctuations in selenium levels compared with other selenoproteins. Mice null for Gpx1 and Gpx2 exhibit severe ileocolitis at a young age and develop microflora-associated cancers in the lower gastrointestinal tract.

GPX1 is polymorphic at codon 198, resulting in either a praline or a leucine at that position, and the frequency of the leu allele is strongly associated with an increase in the risk for lung and possibly breast cancer. The identity of the amino acid at codon 198 (praline or leucine) has functional consequences with regard to level of enzyme activity in response to increasing levels of selenium provided to cells in culture.

Allelic loss of chromosomes regions bearing tumor suppresser genes is a key event in the evolution of epithelial and mesenchymal tumors, and this event can be detected by loss of a heterozygous marker. Loss of heterozygosity (LOH) occurs at the GPX1 locus during the development of several cancer types, including those occurring in lung, breast, and head and neck. In the case of head and neck cancers, GPX1 allelic loss was shown to occur in histopathologically normal tissue adjacent to tumors, indicating that loss at this locus may be an early event in cancer evolution.

CANCER

COLON

GPX1

HUMAN

INCIDENCE

LEVELS

LOSS

SELENIUM

STUDIES

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