Mechanism of Ca(2+)-Dependent Pro-Apoptotic Action of Selenium Nanoparticles, Mediated by Activation of Cx43 Hemichannels

SIMPLE SUMMARY: The development of new methods of anticancer therapy is an urgent task of modern biology. The use of selenium and its compounds as anticancer drugs have already been shown to be effective. At the same time, the problem of selective delivery of selenium to organs and tissues remains. Nanoparticles are a promising and effective form of selenium delivery. This work is devoted to the study of the molecular and cellular mechanisms of action of selenium nanoparticles on glioblastoma cells. Using fluorescence microscopy and PCR, we were able to show for the first time the complete Ca(2+) signaling pathway activated by selenium nanoparticles and the correlation between an increase in Ca(2+) ions in the cytosol of cells with the induction of apoptosis. The presented study contributes to understanding the fundamental mechanisms of activation of programmed cell death in cancer tissue. ABSTRACT: To date, there are practically no data on the mechanisms of the selenium nanoparticles action on calcium homeostasis, intracellular signaling in cancer cells, and on the relationship of signaling pathways activated by an increase in Ca(2+) in the cytosol with the induction of apoptosis, which is of great importance. The study of these mechanisms is important for understanding the cytotoxic effect of selenium nanoparticles and the role of this microelement in the regulation of carcinogenesis. The work is devoted to the study of the role of selenium nanoparticles obtained by laser ablation in the activation of the calcium signaling system and the induction of apoptosis in human glioblastoma cells (A-172 cell line). In this work, it was shown for the first time that the generation of Ca(2+) signals in A-172 cells occurs in response to the application of various concentrations of selenium nanoparticles. The intracellular mechanism responsible for the generation of these Ca(2+) signals has also been established. It was found that nanoparticles promote the mobilization of Ca(2+) ions from the endoplasmic reticulum through the IP(3)-receptor. This leads to the activation of vesicular release of ATP through connexin hemichannels (Cx43) and paracrine cell activation through purinergic receptors (mainly P2Y). In addition, it was shown that the activation of this signaling pathway is accompanied by an increase in the expression of pro-apoptotic genes and the induction of apoptosis. For the first time, the role of Cx43 in the regulation of apoptosis caused by selenium nanoparticles in glioblastoma cells has been shown. It was found that inhibition of Cx43 leads to a significant suppression of the induction of apoptosis in these cells after 24 h treatment of cells with selenium nanoparticles at a concentration of 5 µg/mL.