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.

Fabrication and physicochemical characterization of porous composite microgranules with selenium oxyanions and risedronate sodium for potential applications in bone tumors

“…13 Additionally, numerous studies have declared its chemopreventive and therapeutic activity against various types of cancers. [14][15][16][17] ALG is a natural ionic polymer with l-guluronate and d-mannuronate as major components. It is typically extracted from brown algae (Phaeophyceae).…”

Dynamic equilibrium of endogenous selenium nanoparticles in selenite-exposed cancer cells: a deep insight into the interaction between endogenous SeNPs and proteins

“…When the dynamics of elemental Se were examined in lung cancer A549 cells by extended X-ray absorption fine structure (EXAFS), it was found that the levels of intracellular elemental Se increased between 4 and 72 h, and decreased slightly between 48 and 72 h. 15 As we have revealed that elemental Se in cancer cells presented as SeNPs, 10 we therefore propose that there is a dynamic process of the formation of endogenous SeNPs in cells. In this study, we report the dynamic equilibrium of endogenous SeNP assembly and disassembly in non-small lung cancer H157 cells.…”

“…These results agree with previous studies. 10,21 This growth inhibition is caused by apoptosis, demonstrated by analysis using flow cytometry. 21 …”

“…10 The amount of in vivo Se species has been studied in both cell and animal models. 15,25,26 The percentage of elemental Se detected by EXAFS increased from 37% at 4 h to 55% at 48 h, before decreasing to 49% at 72 h in lung cancer H549 cells.…”

“…Additionally, the surface effects of SeNPs generated oxidative stress, contributing even more to seleniteinduced cytotoxicity. 10 Mitochondria play a central role when responding to selenite toxicity. Cox is a critical enzyme in the mitochondrial electron transport chain and a reduced Cox level may affect mitochondrial structure.…”