Synthetic Na+/K+ exchangers promote apoptosis by disturbing cellular cation homeostasis
Access status:
Open Access
Type
ArticleAuthor/s
Park, Sang-HyunHwang, Inhong
McNaughton, Daniel A.
Kinross, Airlie J.
Howe, Ethan N.W.
Xiong, Shenglun
Kilde, Martin Drøhse
Lynch, Vincent M.
Gale, Philip A.
Sessler, Jonathan L.
Shin, Injae
He, Qing
Abstract
A number of artificial cation ionophores (or transporters) have been developed
for basic research and biomedical applications. However, their mechanisms of
action and the putative correlations between changes in intracellular cation
concentrations and induced cell death remain ...
See moreA number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here we show that three hemispherand-strapped calix[4]pyrrole based ion pair receptors act as efficient Na+/K+ exchangers in the presence of Cl- in liposomal models, and promote Na+ influx and K+ efflux (Na+/K+ exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. The present study provides support for the notion that synthetic receptors which perturb cellular cation homeostasis may provide a new approach to generating agents with potentially useful apoptotic activity.
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See moreA number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here we show that three hemispherand-strapped calix[4]pyrrole based ion pair receptors act as efficient Na+/K+ exchangers in the presence of Cl- in liposomal models, and promote Na+ influx and K+ efflux (Na+/K+ exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. The present study provides support for the notion that synthetic receptors which perturb cellular cation homeostasis may provide a new approach to generating agents with potentially useful apoptotic activity.
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Date
2021Source title
Chemical CommunicationsVolume
7Issue
12Publisher
Cell PressFunding information
ARC DP200100453Licence
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0Faculty/School
Faculty of Science, School of ChemistryThe University of Sydney Multidisciplinary Centres and Institutes , The University of Sydney Nano Institute
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