Extracellular thiol-assisted selenium uptake dependent on the x _c ⁻ cystine transporter explains the cancer-specific cytotoxicity of selenite

Abstract

The selenium salt selenite (SeO3 2؊ ) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x c ؊ antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.2Ϫ ) efficiently inhibits the growth of malignant cells and studies suggest an inverse relationship between resistance to cytotoxic drugs and sensitivity to selenite (SeO 3 2Ϫ ) (1, 2). A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2-8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.With the assumption that the mechanistic explanation is intracellular, studies on differences in cellular uptake have been neglected. Already in the 1960s, selenite (SeO 3 2Ϫ ) was being used experimentally as a tumor-localizing agent. Neoplasms could be detected in brain and thorax in human subjects through i.v. administration of radioactive selenite ( 75 Se) (9). Although at that time the cancer-specific cytotoxic effects of selenite were unknown, and low doses were used (approximately in the nM range in blood) (9), early findings clearly demonstrated that cancer cells enrich selenium in vivo. These findings, combined with current knowledge of selenite's toxic effects on malignant cells, raise the possibility of a cancer-specific high-affinity selenium uptake mechanism that might explain cancer-specific selenite cytotoxicity at therapeutic selenite concentrations (M range).In yeast, millimolar tolerance to selenite can be reduced to the micromolar range by the presence of excessive thiols in the growth medium through high-affinity uptake of a more reduced form of selenite, possibly selenide (10). High-affinity uptake of selenium through the addition of extracellular thiols also has been demonstrated in a keratinocyte model (11) using nanomolar concentrations of selenite. Selenium uptake was prevented in keratinocytes by the ...

Selenium uptake through cystine transporter mediated by glutathione conjugation

“…The possibility that SDG uptake would be increased by extracellular thiol compounds was suggested by a report proposing a mechanism for H 2 SeO 3 uptake assisted by extracellular thiols (Olm et al, 2009). However, instead, we found that SDG uptake was decreased by extracellular thiols.…”

“…These results indicated that SDG is a preferable chemical form, over H 2 SeO 3, for cellular uptake of Se. Olm et al (2009) showed that reductive metabolism by extracellular thiol compounds increased selenite uptake in lung carcinoma cells. These investigators concluded that selenide is the important chemical form for Se uptake, but they did not consider SDG, which is formed during the production of selenide.…”

“…However, in a study using yeast cells, selenite ion (SeO 3 2-) uptake was catalyzed by Jen1p, a transporter for monocarboxylates, such as pyruvate and lactate (McDermott et al, 2010). In lung cancer cells, production of selenide (HSe -/H 2 Se), a membrane permeable selenite metabolite, was dependent on extracellular thiols, primarily cysteine and cystine, whose turnover involves the cystine/glutamate exchange transporter, system x c - (Olm et al, 2009). Such HSe -permeation is related to the cancer-specific toxicity of Se because reported expression of the x c -antiporter was higher in many cancer cells and was correlated with their drug-resistance (Huang et al, 2005;Takeuchi et al, 2013).…”

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

“…The oxidoreductase thioredoxin (Trx) (11) is also up-regulated and involved in the redox remodeling after monocyte activation (8). Up-regulation of the cystine/cysteine redox cycle occurs and serves previously unrecognized signaling and homeostatic functions in different physiological and pathological responses (12), including antigen presentation (13), B cell differentiation (14), and, in cancer cells, resistance to apoptosis (9) and drug sensitivity (15).…”

Selenium in the therapy of neurological diseases. Where is it going?

“…Moreover, the restoration of synaptic proteins, including synaptophysin and postsynaptic density protein 95 in the hippocampus and cortex, and inhibition of inflammatory response were observed in these mice treated with SeMet [130]. A recent study has shown the therapeutic effect of the novel organic Se compound p,p'-methoxyl-diphenyl diselenide (MeOPhSe) 2 against oxidative-nitrosative stress caused by ICV-STZ.…”