Aiming to promote cancer cell apoptosis is a mainstream strategy of cancer therapy. The second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) protein is an essential and endogenous antagonist of inhibitor of apoptosis proteins (IAPs). SMAC mimetics (SMs) are a series of synthetically chemical compounds. Via database analysis and literature searching, we summarize the potential mechanisms of endogenous SMAC inefficiency, degradation, mutation, releasing blockage, and depression. We review the development of SMs, as well as preclinical and clinical outcomes of SMs in solid tumor treatment, and we analyze their strengths, weaknesses, opportunities, and threats from our point of view. We also highlight several questions in need of further investigation.

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.

Cadmium (Cd) is a widespread toxic heavy metal, and exposure to Cd is a growing environmental health concern. The molecular mechanism of Cd cytotoxicity is complicated and still not well understood, and treatment options for Cd cytotoxicity are lacking. Currently, only a limited number of Cd-targeted proteins have been identified. Here, we used Cd-immobilized metal ion affinity chromatography (Cd-IMAC) coupled with LC-MS/MS technique to detect putative Cd-binding proteins in human cells, and nucleophosmin (NPM1) was identified as the top Cd-binding protein. We found that Cd bound exclusively to the methionine/aspartate (M/D)-rich region (MEDSMDMDM) of NPM1, and NPM1 was essential for Cd-induced apoptosis. Furthermore, Cd could trigger intracellular nucleolar stress by causing nucleoplasmic translocation of NPM1 and decreasing pre-rRNA levels through binding to the M/D-rich region of NPM1. Interestingly, we discovered that a short peptide containing only the M/D-rich region of NPM1 could effectively mitigate Cd toxicity, both in vitro and in vivo. Specifically, the synthetic M/D-rich peptide demonstrated significant protection against Cd toxicity, particularly in the liver. It significantly reduced Cd concentration, suppressed the upregulation of blood ALT and AST levels, and alleviated liver inflammation in Cd-exposed BALB/c mice. This study reveals a novel mechanism of Cd cytotoxicity through NPM1-regulated nucleolar stress and apoptosis. Additionally, it identifies a short peptide with strong clinical potential to counteract Cd toxicity.