Selenium induces a multi‐targeted cell death process in addition to ROS formation

Abstract

Selenium compounds inhibit neoplastic growth. Redox active selenium compounds are evolving as promising chemotherapeutic agents through tumour selectivity and multi-target response, which are of great benefit in preventing development of drug resistance. Generation of reactive oxygen species is implicated in selenium-mediated cytotoxic effects on cancer cells. Recent findings indicate that activation of diverse intracellular signalling leading to cell death depends on the chemical form of selenium applied and/or cell line investigated. In the present study, we aimed at deciphering different modes of cell death in a single cell line (HeLa) upon treatment with three redox active selenium compounds (selenite, selenodiglutathione and seleno-DL-cystine). Both selenite and selenodiglutathione exhibited equipotent toxicity (IC50 5 μM) in these cells with striking differences in toxicity mechanisms. Morphological and molecular alterations provided evidence of necroptosis-like cell death in selenite treatment, whereas selenodiglutathione induced apoptosis-like cell death. We demonstrate that selenodiglutathione efficiently glutathionylated free protein thiols, which might explain the early differences in cytotoxic effects induced by selenite and selenodiglutathione. In contrast, seleno-DL-cystine treatment at an IC50 concentration of 100 μM induced morphologically two distinct different types of cell death, one with apoptosis-like phenotype, while the other was reminiscent of paraptosis-like cell death, characterized by induction of unfolded protein response, ER-stress and occurrence of large cytoplasmic vacuoles. Collectively, the current results underline the diverse cytotoxic effects and variable potential of redox active selenium compounds on the survival of HeLa cells and thereby substantiate the potential of chemical species-specific usage of selenium in the treatment of cancers.

Selenium Cytotoxicity in Cancer

“…Furthermore, GS‐Se‐SG at 8 μ M concentration has been shown to selectively induce apoptosis in squamous carcinoma cells compared to normal mucosa cells by induction of Fas‐ligand (Fas‐L) expression, and activation of the stress pathway by increased expression of JNK and p38 . This is also in line with recent findings in our laboratory, where GS‐Se‐SG (5 μ M ) was able to glutathionylate cell surface proteins and induce apoptosis more readily, compared to selenite (5 μ M ) . CysSeSeCys treatment at various concentrations (5–40 μ M ) and time has been reported to induce a S‐phase arrest and apoptosis via ERK and Akt in MCF‐7 cells .…”

Stuck between a ROS and a hard place: Analysis of the ubiquitin proteasome pathway in selenocysteine treated Brassica napus reveals different toxicities during selenium assimilation

“…In human cell lines, selenite, but not Sec, was also shown to result in accumulation of mitochondrial superoxide (Wallenberg et al, 2010) and impair mitochondrial structure (Wallenberg et al, 2014). Additionally, treating human cells with Sec resulted in an increase of Se in protein, and this was associated with an unfolded protein selenite selenite selenocysteine selenoprotein Selenium assimil ation p athway transl ation misfolded p rotein reactive oxygen species…”

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

“…Overall, these results implied that SeCys formation plays a central role in SeMet-induced growth inhibition, which suggests that SeMet mode of action should be similar to that of SeCys. In this context, it is interesting to note that, in a recent study by Kupsco and Schlenk (146), exposure of fish (Japanese medaka) embryos to SeMet combined with hypersalinity induced a 100-fold increase in transcripts of BiP, the major ER chaperone (146), suggesting an accumulation of misfolded proteins in the ER reminiscent of the SeCystine-induced ER stress observed by Wallenberg et al (120) in HeLa cells.…”

“…The same authors showed that SeCystine triggered endoplasmic reticulum (ER) stress, the unfolded protein response, an increase in protein ubiquitination and extensive cytoplasmic vacuolarization in HeLa cells, in the absence of DNA damage (120). In higher plants also, evidence was recently provided that SeCys treatment impairs protein homeostasis without elevation of superoxide levels (121,122).…”