Selenium Sword Of Damocles - The Proliferation Of Human Cancer Cells To Induce High Maternal Dietary Selenium And Its Progeny Glucose Metabolism And Suppress Pig Serum Se

Diabetes and cancer are a major public health concern that affects millions of people worldwide. Selenium is an essential trace element that acts as a double-edged sword in anticancer and glucose metabolism disorders. These disorders may therefore act through the Se dependent selenoproteins. It is therefore extremely important to explore the mechanisms behind the effects of selenium or selenoproteins. Our objectives of the present study were to study the mechanism of high selenium induced glucose metabolism disorder in mice and their offspring as well as Se-biofortified porcine serum on human cancer cells proliferation.Study1. Study of the mechanism of high selenium induced glucose metabolism disorder in mice and their offspringWe previously reported type2diabetes-like phenotypes in glutathione peroxidase-1(GPX1)-overexpressing mice (OE) and gestational diabetes in rats fed a high-Se (3mg/kg) diet. The Expt.1was to determine if these two factors induced and(or) exacerbated gestational diabetes in mice. An experiment was conducted with3genotypes of mice:OE, GPX1-/-, and wild-type (WT)(2-6mo, females, n=12per genotype by treatment) and2levels of dietary Se:0.4or1.0mg Se/kg (as sodium selenite in a Torula-yeast based diet) from3wk before breeding to d21postpartum. Genotypes affected (P<0.05) body weight, blood glucose, plasma insulin, and glucose and insulin tolerances at all4tested time-points. While the OE mice had elevated (P<0.05) body weight, blood glucose and plasma insulin compared with the WT and GPX1-/-mice, they showed better glucose tolerance throughout and improved insulin sensitivity on d19of gestation. Interestingly, plasma insulin was significantly decreased90%, while blood glucose had decreased only15%in GPX-/-mice on d19of gestation when compared to WT and OE mice.The high Se diet was hyperinsulinemic and hypoglycemic (P<0.05) and impaired insulin and glucose tolerances in the WT and OE mice on d19of gestation and(or) d10postpartum. The WT offspring were also prone to developing insulin resistance and impared glucose tolencence on the high Se diet. The high Se diet also decreased expression of insulin synthesis and signaling-related genes and proteins in islets, liver, and muscle of the WT and OE mice. In conclusion, although high dietary Se intake did not induce overt gestational diabetes in the OE mice, knockout of GPX1constrained adverse effects of high Se in this regard.Expt.1showed plasma insulin significantly decreased90%, while blood glucose decreased only15%in GPX-/-mice on d19of gestation when compared to WT and OE mice. Expt.2was designed to explore the mechanisms of glucose metabolism disorder in GPX-/-mice during the third trimester. An experiment was conducted with2genotypes of mice:GPX1-/-and wild-type (WT)(2-6mo, females, n=12) and placed on a0.4mg Se/kg (as sodium selenite in a Torula-yeast based diet) diet from3weeks before breeding to d19gestation. The plasma insulin was determined by high performance liquid chromatographic (HPLC) and resulted in a67%decrease in GPX-/-mice on d19of gestation. The retention time dose had not changed when compared with WT mice however. Blood glucose had also decreased15%in GPX-/-mice, which was consistent with Expt.1. The crucial importance of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) was also decreased in GPX-/-mice. Reduced glutathione (GSH), partially degraded insulin, was increased in GPX-/-mice. The insulin synthesis and secretion-related genes and proteins in islets have no significant changes. In conclusion, the signicantly low levels of plasma insulin in GPX-/-mice during the third trimester partially due to increase the oxidation stress regulated GSH in liver.Study2. Study of the mechanism of Se-biofortified porcine serum on human cancer cells proliferationOur objectives were to determine if porcine serum could be enriched with Se by feeding pigs with high levels of dietary Se and if the Se-biofortified serum inhibited proliferation of two types of human cancer cells. Growing pigs (5-wk old, n=6) were fed0.3mg Se/kg or1.0mg Se/kg (as Se-enriched yeast) for6wk and produced serum with2.6and6.2μM Se, respectively. After the Se biofortified porcine sera were added at16%in RPMI1640to treat DU145and HTC116cells for144h, they decreased (P<0.05) viability of the two types of human cancer cells by promoting apoptosis, compared with their controls. This effect was replicated by only appropriate amount of methylseleninic acid added to the control serum, and was mediated by a down-regulation of8cell cycle arrest genes and an up-regulation of7apoptotic genes. Along with6previously-reported selenoprotein genes, Sell, Selm, Selh, Selk, and Sepnl were revealed to be strongly associated with the cell death-related signaling induced by the Se-enriched porcine serum. In conclusion, porcine serum could be biofortified with Se to effectively inhibit proliferation of three types of human cancer cells, and the action was correlated with a matrix of coordinated functional expression of multiple selenoprotein genes.