Abstract
The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.
Highlights
Selenium (Se) is an essential micronutrient critical for maintaining normal cellular function in human and animal cells [1]
McDermott et al [17] used multiple model systems to study the Se transport ability of ZIP8, and they showed that Se uptake was closely associated with ZIP8 expression in all the models tested, including cell cultures and transgenic mice
Unlike McDermott et al [17] where the ZIP8 expression of arsenic-transformed human bronchial epithelial BEAS-2B cells was knockdown by shRNA, in the current study, we used CRISPR/Cas9-based KO system to eliminate the endogenous expression of ZIP8 in the Human cervical cancer (HeLa) cells
Summary
Selenium (Se) is an essential micronutrient critical for maintaining normal cellular function in human and animal cells [1] It is an integral component of selenoproteins which are involved in a wide range of cellular physiological processes, including but not limited to antioxidant defense, inflammatory response, immune regulation, and maintenance of cardiovascular and reproductive system [2,3,4]. Se and Se compounds have displayed promising anticancer activity against some cancer cell types [11]. None of these compounds have yet been clinically recognized as anticancer agents mostly due to inconsistent outcomes within and between clinical trials and laboratory studies [12,13,14]. Se compounds may be useful in the field of chemoprevention as it has been reported that Se could potentiate the efficacy of some chemotherapeutic drugs, for example, the first-line chemotherapeutic drug cisplatin [15]
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