title: Reduction of selenium-binding protein 1 sensitizes cancer cells to selenite via elevating extracellular glutathione: a novel mechanism of cancer-specific cytotoxicity of selenite.
abstract: Selenium is an essential trace element and has been extensively studied for preventive effects on cancers. Recent emerging evidence has also shown that selenium at supranutritional 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 nontumor tissues (Pearson r=-0.4347, P=0.0338). Ectopic expression of GPX1 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 on 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 the extracellular microenvironment by regulating the levels of extracellular GSH.
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China; Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, Hubei, 430071, China.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China; Department of Oncology, the Fifth Hospital, Wuhan, Hubei, 430051, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Illinois at Chicago, IL 60612, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ying
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, China; Department of Pathology, University of Illinois at Chicago, IL 60612, USA. Electronic address: wyang06@uic.edu.
authors.forename: Wancai
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China; Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, Hubei, 430071, China. Electronic address: Binxiong1961@gmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Xiong
mesh_terms: D005110:Extracellular Space / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000473:pathology*; D020887:Selenious Acid / Q000494:pharmacology*; D051137:Selenium-Binding Proteins / Q000378:metabolism*
chemical_list: C495175:SELENBP1 protein, human; D051137:Selenium-Binding Proteins; D020887:Selenious Acid; D005978:Glutathione
keywords: Breast cancer; Cytotoxicity; Glutathione; Glutathione peroxidase 1; Hydrogen peroxide; Reactive oxygen species; Selenite; Selenium-binding protein 1; Selenium-containing protein; Superoxide anion