Mechanism of Ca2+-Dependent Pro-Apoptotic Action of Selenium Nanoparticles, Mediated by Activation of Cx43 Hemichannels

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 Ca2+ 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 Ca2+ 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 Ca2+ signals has also been established. It was found that nanoparticles promote the mobilization of Ca2+ ions from the endoplasmic reticulum through the IP3-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.

Targeted Nanoparticle Photodynamic Diagnosis and Therapy of Colorectal Cancer

“…In relation to future research, investigations into the cellular signaling pathways, which were affected post-BNC PDT treatment to induce the noted significant forms of apoptotic programmed cell death, require additional understanding. With reference to studies conducted by Turovsky and Varlamova (2021), these types of future studies will contribute to the understanding of the fundamental mechanisms of activation that promote programmed cell death in CRC tissues [55]. Furthermore, similar studies, such as those conducted by Varlamova et al (2021), require additional research, whereby the sensitivity and intensity of CRC cell death post-PDT, in relation to BNC concentration, is investigated in order to fully elucidate and understand the molecular mechanisms that regulate these PDT cytotoxic effects [56].…”

Therapeutic Potential and Main Methods of Obtaining Selenium Nanoparticles

“…The mechanism of increasing Ca 2+ ions in the cytosol involves the activation of IP 3 receptors, mobilization of Ca 2+ from the ER, and activation of intercellular communication through connexin channels and paracrine ATP secretion ( Figure 3 ). This increase in [Ca 2+ ] i leads to a change in the expression profile of gene encoding proteins responsible for the induction of apoptosis [ 156 ]. Increased expression of the pro-apoptotic genes CHOP, GADD34 BIM, PUMA, and BAX indicates the activation of apoptosis through the mitochondrial pathway.…”

Diazoxide Needs Mitochondrial Connexin43 to Exert Its Cytoprotective Effect in a Cellular Model of CoCl2-Induced Hypoxia

“…During stress conditions, Cx43 translocates to the mitochondria with a mechanism that involves the Hsp90/Tom20 machinery system [ 4 , 7 ], and many studies conducted using the Hsp90 inhibitor radicicol supported this theory [ 8 , 9 , 10 ]. Mitochondrial Cx43 (mCx43) acts as an important regulator of apoptosis, allowing the passage of molecules that induce apoptosis such as Ca 2+ , IP 3 and cAMP ions [ 11 ] and influencing mitochondrial respiration, matrix ion fluxes and ROS production [ 9 ]. Indeed, mitochondria are at the same time the most powerful intracellular source and the primary target for damaging effects of ROS.…”