Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice

Sergey V Novoselov,Bradley A Carlson,Mohamed E Moustafa,Valentina M Factor,Vadim N Gladyshev,Dmitri E Fomenko,Vyacheslav M Labunskyy,Dolph L Hatfield,Diego F Calvisi

doi:10.1038/sj.onc.1208940

Abstract

The micronutrient element selenium (Se) has been shown to be effective in reducing the incidence of cancer in animal models and human clinical trials. Selenoproteins and low molecular weight Se compounds were implicated in the chemopreventive effect, but specific mechanisms are not clear. We examined the role of Se and selenoproteins in liver tumor formation in TGFalpha/c-Myc transgenic mice, which are characterized by disrupted redox homeostasis and develop liver cancer by 6 months of age. In these mice, both Se deficiency and high levels of Se compounds suppressed hepatocarcinogenesis. In addition, both treatments induced expression of detoxification genes, increased apoptosis and inhibited cell proliferation. Within low-to-optimal levels of dietary Se, tumor formation correlated with expression of most selenoproteins. These data suggest that changes in selenoprotein expression may either suppress or promote tumorigenesis depending on cell type and genotype. Since dietary Se may have opposing effects on cancer, it is important to identify the subjects who will benefit from Se supplementation as well as those who will not.

Highlights

The micronutrient element selenium (Se) has been shown to be effective in reducing the incidence of cancer in animal models and human clinical trials (Clark et al, 1996; Yu et al, 1997; Yoshizawa et al, 1998; Milner et al, 2001; Ip et al, 2002)
By performing metabolic labeling of mice with 75Se, we analysed the distribution of selenoproteins by SDS– PAGE in transforming growth factor alpha (TGFa)/c-Myc mice at the early dysplastic stage (10 weeks) and tumor stage (27 weeks) (Supplementary Figure S1)
In the tumors derived from 6-month-old mice, expression of glutathione peroxidase 1 (GPx1; a major 25 kDa 75Se-labeled band) was significantly reduced, whereas expression of thioredoxin reductase 1 (TR1; a 55 kDa 75Se-labeled band) appeared to be slightly elevated (Supplementary Figure S1)

Summary

Introduction

The micronutrient element selenium (Se) has been shown to be effective in reducing the incidence of cancer in animal models and human clinical trials (Clark et al, 1996; Yu et al, 1997; Yoshizawa et al, 1998; Milner et al, 2001; Ip et al, 2002). One considers that the chemopreventive action of dietary Se is mediated by an increased abundance in Se-containing proteins, while the other that low molecular weight Se-containing compounds (or selenocompounds) are responsible for the chemopreventive effect (Ganther, 1999; Whanger, 2004). The term of low molecular weight selenocompounds refers to Se-containing organic and inorganic compounds that have potent cancer prevention potential. Whether selenoproteins may provide the protection against cancers at an optimal nutritional concentration of Se, and low molecular weight Se compounds at higher concentration, is not known

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