Abstract
Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta–Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.
Highlights
Selenium (Se) is an essential trace element found in all mammals and is vital for the proper functioning of selenoproteins, a unique group of proteins containing the rare but required amino acid, selenocysteine
Possible Mechanisms of Selenite Regulated Notch Signaling when applied in tissue lysate, did not probe like it did for cell lysates at the correct size
ZIP8 knockout cultured in a Se-deficiency media, The probedhepatocytes a band at lower molecular weight, around
Summary
Selenium (Se) is an essential trace element found in all mammals and is vital for the proper functioning of selenoproteins, a unique group of proteins containing the rare but required amino acid, selenocysteine. Many selenoproteins including glutathione peroxidase (GPX) and thioredoxin reductase (TR) are antioxidants responsible for detoxifying reactive superoxide species (ROS) [1]. Selenium exists in both organic and inorganic forms with distinct cellular functions and toxicity. The organoselenium compounds such as methylselenocysteine and selenomethionine have been extensively studied and shown to be potent inhibitors of angiogenesis and cancers at supra-nutritional doses [2,3]. One form of inorganic selenium, anionic selenite (H2 SeO3 , dominantly HSeO3 − in physiological pH), has been clinically adopted to treat Keshan disease. Selenite supplemented via diet effectively rescues the symptoms observed in Keshan disease, indicating selenite’s potential to serve a wide range of biological functions
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