Selenium uptake through cystine transporter mediated by glutathione conjugation

Abstract

-Selenium (Se) is an essential trace element and is regarded as a protective agent against cancer. In particular, antioxidant effects of selenoenzymes contribute to cancer prevention. Se can also produce reactive oxygen species and, thereby, exert cancer-selective cytotoxicity. Selenodiglutathione (SDG) is a primary Se metabolite conjugated to two glutathione (GSH) moieties. SDG increases intracellular Se accumulation and is more toxic than selenous acid (H 2 SeO 3 ), but the mechanisms for importing Se compounds into cells are not fully understood. Here, we propose a novel mechanism for importing Se, in the form of SDG. Cellular intake of Se compounds was assessed based on Se accumulation, as detected by ICP-MS. SDG incorporation was decreased in the presence of thiols (GSH, cysteine or their oxidized forms, GSSG and cystine), whereas H 2 SeO 3 uptake was increased by addition of GSH or cysteine. Cellular SDG uptake was decreased by pretreatment with specific inhibitors against gamma-glutamyl transpeptidase (GGT) or the cystine/glutamate antiporter (system x c -). Furthermore, siRNA against xCT, which is the light chain component of system x c -, significantly decreased SDG incorporation. These data suggest an involvement of SDG in Se incorporation, with SDG processed at the cell surface by GGT, leading to formation of selenodicysteine which, in turn, is likely to be imported via xCT. Because GGT and xCT are highly expressed in cancer cells, these mechanisms mediated by the cystine transporter might underlie the cancer-selective toxicity of Se. In addition, the system described in our study appears to represent a physiological transport mechanism for the essential element Se.

Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation

“…As selenium is also transported by xCT [23,43], we hypothesized that selenium compounds are able to impair cysteine uptake. Albeit having antioxidant properties, selenium can also function as a pro-oxidant and exhibit toxicity toward tumor cells [40,42]. In the present study, we focused on the selenium–chrysin (SeChry) compound [42,48], which was described as having anti-tumor effects, even without selenium [42,48,49].…”

“…Selenium (Se) is an essential element required for the maintenance of cellular redox balance [40,41] by being a cofactor of mammalian enzymes such as glutathione peroxidase [40,42]. In addition, selenium compounds are taken up by cyst(e)ine transporters [40,43,44], and some studies demonstrated that selenium itself exerts anti-tumoral activity [45,46]. In accordance, in small-cell lung cancer cell lines, xCT activity was related to higher selenium salt (selenite) sensitivity [47], revealing the possible use of xCT as a mediator of therapies based on selenium.…”

Selenium Toxicity Accelerated by Out-of-Control Response of Nrf2-xCT Pathway

“…The resulting compound, selenodicysteine (CSSeSC), is taken into the cell by xCT. 17) In the cell, CSSeSC undergoes sequential metabolisms into hydrogen selenide (H 2 Se) by GSH and finally oxidizes to elemental Se, accompanied with ROS generation. 21) This oxidative stress induces protective cellular responses, including xCT upregulation, as observed in Fig.…”

“…We recently identified evidence that GSSeSG enters into cells more rapidly than selenite through an amino acid transporter xCT. 17) xCT is coded on the SLC7A11 gene and constitutes the cystine/glutamate exchange system x c -that supplies cysteine necessary for GSH biosynthesis. 18) Cells increase GSH synthesis by upregulating xCT expression to cope with reactive oxygen species (ROS).…”

Baicalin protects against APEC-induced colibacillosis by regulating gut microbiota and its metabolites in Chickens

“…Gentamicin C1a is considered as a precursor to the synthesis of etimicin (Wei et al, 2019). Selenodiglutathione is a primary Se metabolite conjugated to two glutathione moieties, and it increase intracellular Se accumulation and is more toxic than selenous acid (Fisher et al, 2016;Tobe et al, 2017). L-arabinose, a kind of plant-specific five-carbon aldose, is a naturally occurring constituent of plant polysaccharides, and often extracted from vegetable gum, corn straw or beet (Feher, Gal, Feher, Barta, & Reczey, 2015;Kotake, Yamanashi, Imaizumi, & Tsumuraya, 2016;Moremi, Jansen Van Rensburg, & La Grange, 2020).…”