Selenite Inhibits Notch Signaling in Cells and Mice

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.

Therapeutic Benefits of Selenium in Hematological Malignancies

“…These studies have shown that, at supra-nutritional concentrations, MSC and SLM exhibit anti-angiogenic and anti-cancer effects. The well-studied inorganic selenium compound selenite ( Figure 2 ) is clinically utilized and supplemented in the diet of patients with the endemic Keshan disease [ 61 , 62 ]. Keshan disease arises due to insufficient dietary selenium levels, which can result in cardiovascular atrophy if not properly addressed [ 61 , 62 ].…”

“…The well-studied inorganic selenium compound selenite ( Figure 2 ) is clinically utilized and supplemented in the diet of patients with the endemic Keshan disease [ 61 , 62 ]. Keshan disease arises due to insufficient dietary selenium levels, which can result in cardiovascular atrophy if not properly addressed [ 61 , 62 ]. The supplementation of selenite into the diet successfully treats Keshan disease and the associated symptoms, suggesting the therapeutic benefits that can be imparted by selenite [ 61 , 62 ].…”

“…Keshan disease arises due to insufficient dietary selenium levels, which can result in cardiovascular atrophy if not properly addressed [ 61 , 62 ]. The supplementation of selenite into the diet successfully treats Keshan disease and the associated symptoms, suggesting the therapeutic benefits that can be imparted by selenite [ 61 , 62 ].…”

“…Selenium-derived compounds have been shown to alter the expression of various target genes or modulate the interplay between signaling networks [ 83 , 114 ]. Powers and co-workers demonstrated that selenium supplementation in the form of selenite plays a role in cellular signaling and its consequences by regulating the highly conserved Delta–Notch signaling pathway [ 61 ]. In vitro studies indicated that selenite treatment on primary mouse hepatocytes, MCF7 breast adenocarcinoma cells, or HEPF2 liver carcinoma cells altered the transcription levels of various genes involved in the Delta–Notch signaling network (e.g., Notch1) [ 61 ].…”

“…Powers and co-workers demonstrated that selenium supplementation in the form of selenite plays a role in cellular signaling and its consequences by regulating the highly conserved Delta–Notch signaling pathway [ 61 ]. In vitro studies indicated that selenite treatment on primary mouse hepatocytes, MCF7 breast adenocarcinoma cells, or HEPF2 liver carcinoma cells altered the transcription levels of various genes involved in the Delta–Notch signaling network (e.g., Notch1) [ 61 ]. The intraperitoneal administration of selenite (2.5 mg/kg) to mice resulted in significantly reduced Notch1 expression levels in liver and kidney tissues [ 61 ].…”