title: 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 (H2SeO3), 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 H2SeO3uptake 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 xc-). Furthermore, siRNA against xCT, which is the light chain component of system xc-, 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.
authors.affiliation: Faculty of Pharmacy, Meijo University.
authors.forename: Takao
authors.initials: T
authors.lastname: Tobe
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.forename: Akira
authors.initials: A
authors.lastname: Aoki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Nakao
authors.initials: N
authors.lastname: Kojima
authors.forename: Hideto
authors.initials: H
authors.lastname: Jinno
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D016566:Organoselenium Compounds / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D020887:Selenious Acid / Q000494:pharmacology*; D012643:Selenium / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D016566:Organoselenium Compounds; D034741:RNA, Small Interfering; C118895:SLC7A11 protein, human; C017710:selenodiglutathione; D005723:gamma-Glutamyltransferase; D020887:Selenious Acid; D005978:Glutathione; D012643:Selenium