title: Selenite-induced toxicity in cancer cells is mediated by metabolic generation of endogenous selenium nanoparticles.
abstract: Selenite has been a touted cancer chemopreventative agent but generates conflicting outcomes. Multiple mechanisms of selenite cytotoxicity in cancer cells are thought to be induced by metabolites of selenite. We observed that intracellular metabolism of selenite generates endogenous selenium nanoparticles (SeNPs) in cancer cells. Critical proteins that bind with high affinity to elemental selenium during SeNPs self-assembly were identified through proteomics analysis; these include glycolytic enzymes, insoluble tubulin, and heat shock proteins 90 (HSP90). Sequestration of glycolytic enzymes by SeNPs dramatically inhibits ATP generation, which leads to functional and structural disruption of mitochondria. Transcriptome sequencing showed tremendous down-regulation of mitochondrial respiratory NADH dehydrogenase (complex I), cytochrome c oxidase (complex IV), and ATP synthase (complex V) in response to glycolysis-dependent mitochondrial dysfunction. Sequestration of insoluble tubulin led to microtubule depolymerization, altering microtubule dynamics. HSP90 sequestration led to degradation of its downstream effectors via autophagy, ultimately resulting in a cell-signaling switch to apoptosis. Additionally, the surface effects of SeNPs generated oxidative stress, thus contributing to selenite cytotoxicity. Herein, we reveal that the multiple mechanisms of selenite-induced cytotoxicity are caused by endogenous protein-assisted self-assembly of SeNPs and suggest that endogenous SeNPs could potentially be the primary cause of selenite-induced cytotoxicity.
authors.affiliation: State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , 18 Shuangqing Road, Haidian District, Beijing 100085, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Bao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Ren-Zhong
authors.initials: RZ
authors.lastname: Tai
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
authors.forename: Yong-Guan
authors.initials: YG
authors.lastname: Zhu
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D006019:Glycolysis; D006801:Humans; D053768:Metal Nanoparticles; D058105:Polymerization; D017382:Reactive Oxygen Species / Q000378:metabolism; D020887:Selenious Acid / Q000633:toxicity*; D012643:Selenium / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D020887:Selenious Acid; D012643:Selenium
keywords: chemoprevention; glycolysis; heat shock proteins; mitochondrial dysfunction; selenite; selenium nanoparticles; self-assembly; tubulin