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Selenium induces a multi-targeted cell death process in addition to ROS formation
Marita Wallenberg1, Sougat Misra, Agata M Wasik
1Division of Pathology F46, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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.
Insights
Redox-active selenium compounds like selenite, selenodiglutathione, and seleno-DL-cystine induce distinct cell death pathways in HeLa cancer cells. This highlights the potential for species-specific selenium chemotherapeutics to combat cancer drug resistance.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Redox-active selenium compounds show promise as chemotherapeutics due to tumor selectivity and multi-target responses, potentially overcoming drug resistance.
- Selenium's cytotoxic effects on cancer cells involve reactive oxygen species generation and diverse intracellular signaling pathways.
- The specific chemical form of selenium and the cell line influence the mode of cell death induced.
Purpose of the Study:
- To investigate and differentiate the cell death mechanisms induced by three redox-active selenium compounds (selenite, selenodiglutathione, and seleno-DL-cystine) in HeLa cancer cells.
- To elucidate the role of chemical species-specific selenium compounds in cancer cell survival and potential therapeutic applications.
Main Methods:
- Treatment of HeLa cells with varying concentrations of selenite, selenodiglutathione, and seleno-DL-cystine.
- Morphological and molecular analyses to identify distinct cell death phenotypes (apoptosis, necroptosis, paraptosis).
- Assessment of protein thiol glutathionylation and endoplasmic reticulum (ER) stress markers.
Main Results:
- Selenite and selenodiglutathione demonstrated equipotent toxicity (IC50 5 μM) but induced different cell death pathways: necroptosis-like (selenite) and apoptosis-like (selenodiglutathione).
- Selenodiglutathione induced significant glutathionylation of free protein thiols.
- Seleno-DL-cystine (IC50 100 μM) induced two distinct cell death modes: apoptosis-like and paraptosis-like, characterized by ER stress and cytoplasmic vacuolation.
Conclusions:
- The study reveals diverse cytotoxic effects and cell death mechanisms of different redox-active selenium compounds in HeLa cells.
- Findings underscore the potential for tailored, chemical species-specific selenium therapies in cancer treatment.
- Understanding these distinct pathways is crucial for developing effective selenium-based anticancer strategies and preventing drug resistance.
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