Molecular Mechanisms Underlying The Role For Selenium-binding Protein 1 In Suppressing The Malignant Characteristics Of Cancer Cells And In Mediating The Cancer-Specific Cytotoxicity Of Selenite

Part Ⅰ:Molecular Mechanisms Responsible for the Tumor Suppressive Role of SBPl in Human Cancer CellsEmerging evidences have shown that the levels of selenium-binding protein 1 (SBP1) are frequently down-regulated or even lost in various cancer tissues as compared to the corresponding normal tissues, implicating SBP1 as a potential tumor suppressor. However, the molecular mechanisms underlying the tumor suppressive role for SBP1 in cancer cells are still largely unknown. In the present study, we investigated the expression levels of SBP 1 in human bladder cancer tissues and cell lines, and explored the role of SBP1 and the underlying molecular mechanisms in malignant cells including human bladder and colorectal cancer cells. Firstly, we found that the expression levels of SBP1 were markedly reduced in human bladder cancer tissues and cells lines in comparison with adjacent matched normal tissues. Consistent with previous studies, over-expression of SBP1 significantly suppressed the cell growth and invasiveness in human cancer cells. Furthermore, ectopic expression of SBP1 pronouncedly attenuated the phosphorylation of c-Jun and STAT1, both of which have been identified to be essential for SBP1-mediated transcriptional induction of p21, thereby resulting in the G0/G1 phase arrest in cancer cells. Additionally, we found that MMP2 was a critical player that mediated the inhibitory role of SBP1 in cancer cell invasion. Ectopic expression of SBP1 led to a remarkable decrease in MMP2 expression as a result of up-regulation of AUF1, which specifically targeted the ARE sites in MMP2-3’-UTR and caused the destabilization of MMP2 mRNA. Taken together, our findings provided novel mechanistic insights into the understanding of the tumor suppressive role for SBP 1 in tumorigenesis, suggesting that SBP 1 could potentially be used as therapeutic target in cancer therapy.Part Ⅱ:Molecular Mechanisms Underlying the Role of SBP1 in Cancer-Specific Cytotoxicity of SeleniteSelenium is an essential trace element and has been extensively studied for preventive effects on cancers. Recent emerging evidences have also shown that selenium at supra-nutritional dosage has a preferential cytotoxicity in cancer cells and chemotherapeutic drug-resistant cells, but the underlying mechanisms remain largely unknown. This study was to investigate the roles of two distinct representatives of selenium-containing proteins, selenium- binding protein 1 (SBP1) and glutathione peroxidase 1 (GPX1), in selenite-mediated cancer-specific cytotoxicity. We found that there was a significantly inverse correlation between SBP1 and GPX1 protein level in human breast cancers and adjacent matched non-tumor tissues (Pearson r=-0.4347, P=0.0338). Ectopic expression of GPXl enhanced selenite cytotoxicity through down-regulation of SBP1, and SBP1 was likely to be a crucial determinant for selenite-mediated cytotoxicity. Reduction of SBP1 in cancer cells and epirubicin-resistant cells upon selenite exposure resulted in a dramatic increase in the generation of hydrogen peroxide and superoxide anion, which in turn caused oxidative stress and triggered apoptosis. Furthermore, knockdown SBP1 by small interfering RNA increased selenite sensitivity by elevating extracellular glutathione (GSH), which spontaneously reacted with selenite and led to the rapid depletion of selenium (Ⅳ) in growth medium and the high-affinity uptake of selenite. In conclusion, these findings would improve our understanding of the roles of selenium-containing proteins in selenite-mediated cytotoxicity, and revealed a potent mechanism of the selective cytotoxicity of selenite in cancer cells and drug-resistant cells, in which SBP1 was likely to play an important role in modulating extracellular microenvironment by regulating the levels of extracellular GSH.