Abstract
Methylselenol (MeSeH) is a major cytotoxic metabolite of selenium, causing apoptosis in cancer cells through mechanisms that remain to be fully established. Previously, we demonstrated that, in Saccharomyces cerevisiae, MeSeH toxicity was mediated by its metabolization into selenomethionine by O-acetylhomoserine (OAH)-sulfhydrylase, an enzyme that is absent in higher eukaryotes. In this report, we used a mutant met17 yeast strain, devoid of OAH- sulfhydrylase activity, to identify alternative targets of MeSeH. Exposure to dimethyldiselenide (DMDSe), a direct precursor of MeSeH, caused an endoplasmic reticulum (ER) stress, as evidenced by increased expression of the ER chaperone Kar2p. Mutant strains (∆ire1 and ∆hac1) unable to activate the unfolded protein response were hypersensitive to MeSeH precursors but not to selenomethionine. In contrast, deletion of YAP1 or SKN7, required to activate the oxidative stress response, did not affect cell growth in the presence of DMDSe. ER maturation of newly synthesized carboxypeptidase Y was impaired, indicating that MeSeH/DMDSe caused protein misfolding in the ER. Exposure to DMDSe resulted in induction of the expression of the ER oxidoreductase Ero1p with concomitant reduction of its regulatory disulfide bonds. These results suggest that MeSeH disturbs protein folding in the ER by generating a reductive stress in this compartment.
Highlights
During the last decades, extensive research has been focused on the identification of selenium (Se) compounds exhibiting cancer chemo-preventive properties [1]
The results indicate that exposure to toxic concentrations of SeMet, resulting in a 20–50% reduction of the growth rate, 5 ofin12 creased the expression of SSA4, a target of Hsf1p, but was unable to trigger either an oxidative or endoplasmic reticulum (ER) stress response
We show that exposure to these compounds triggered absence of these bonds can be readily discerned by mobility differences on nonreducing the activation of the unfolded protein response (UPR)
Summary
Extensive research has been focused on the identification of selenium (Se) compounds exhibiting cancer chemo-preventive properties [1]. MeSeH, generated in vitro from selenomethionine (SeMet) and methioninase, was shown to redox cycle with GSH and oxygen, producing superoxides that were proposed to account for oxidative stress-induced cytotoxicity [10]. We showed that MeSeH toxicity was mainly mediated by its metabolization into SeMet by O-acetylhomoserine (OAH)-sulfhydrylase followed by the conversion of SeMet into selenocysteine (SeCys) by the transsulfuration pathway resulting in SeCys misincorporation during protein synthesis, inducing toxic protein aggregation. This mechanism is not likely to account for MSeA anticancer effects because human cells lack OAH-sulhydrylase activity. In this strain, toxicity of the MeSeH precursor DMDSe is caused by an accumulation of misfolded proteins in the ER
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