Intracellular Ca2 + Imbalance Critically Contributes to Paraptosis

Abstract

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process. Ca2+ transport has been shown to be important in the paraptosis induced by several natural products, metal complexes, and co-treatment with proteasome inhibitors and certain Ca2+-modulating agents. In particular, the Ca2+-mediated communication between the ER and mitochondria plays a crucial role in paraptosis. Mitochondrial Ca2+ overload from the intracellular Ca2+-flux system located at the ER–mitochondrial axis can induce mitochondrial dilation during paraptosis, while the accumulation of misfolded proteins within the ER lumen is believed to exert an osmotic force and draw water from the cytoplasm to distend the ER lumen. In this process, Ca2+ release from the ER also critically contributes to aggravating ER stress and ER dilation. This review focuses on the role of Ca2+ transport in paraptosis by summarizing the recent findings related to the actions of Ca2+-modulating paraptosis-inducing agents and discussing the potential cancer therapeutic strategies that may effectively induce paraptosis via Ca2+ signaling.

The Isoxazole Derivative of Usnic Acid Induces an ER Stress Response in Breast Cancer Cells That Leads to Paraptosis-like Cell Death

“…This happens in the absence of caspase activation and other apoptotic markers, such as significant cell membrane blebbing or nuclear shrinkage and pyknosis [40,41]. Paraptosis is often accompanied by an alteration of Ca 2+ and disruption of redox or ER homeostasis [42]. Not all these features are always observed in cells undergoing paraptosis, and thus the term "paraptosis-like cell death" is used when cell death resembles paraptosis but lacks some of its symptoms [43,44].…”

“…Not all these features are always observed in cells undergoing paraptosis, and thus the term "paraptosis-like cell death" is used when cell death resembles paraptosis but lacks some of its symptoms [43,44]. Many natural products, as well as developed compounds, have also been shown to induce paraptosis in cancer cells by disruption of calcium homeostasis [42]. Maintenance of calcium homeostasis in the ER is crucial for protein folding and the functioning of enzymes and chaperones [45], and its release by IP3Rs or RyRs may lead to the accumulation of misfolded proteins within the ER lumen that exert an osmotic force for the influx of water from the cytoplasm, and thus ER swelling [46].…”

Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca2+ Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential

“…On the other hand, ER stress markers had a negligible effect after treatment with celastrol (Figure 13D), which increases cytoplasmic Ca 2+ concentrations to induce paraptosis in Jurkat cells, suggesting that ASb-2 and celastrol induce paraptosis via different signaling pathways. It has been reported that the ER and mitochondria are main reservoirs for intracellular Ca 2+ [73] and that damage to the ER and mitochondria by Ca 2+ distribution, Ca 2+ overload, and a loss of Ca 2+ homeostasis induces cytotoxicity, oxidative stress, and mitochondrial dysfunction, resulting in PCD such as paraptosis [77], although the molecular target of ASb-2 has not been precisely identified. It was also found that curcumin increases cytoplasmic and mitochondrial Ca 2+ concentrations and ER stress to induce apoptosis in Jurkat cells (Figure 9C,D and Figure 13E,F).…”

PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance

“…We herein show for the first time that pharmacological or genetic inhibition of PSMD14 in several breast cancer cells induces paraptosis as a major cell death mode. Although the molecular basis of paraptosis remains to be further elucidated in detail, disruption of proteostasis (including proteasome inhibition) and Ca 2+ imbalance have been proposed as the underlying mechanisms of paraptosis [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 25 ]. The vacuolization observed during paraptosis is believed to result from an influx of water into the ER and mitochondria, which occurs due to the increase in osmotic pressure induced by the accumulation of misfolded proteins within these organelles [ 14 , 25 ] or Ca 2+ overload in mitochondria [ 16 , 21 , 22 ].…”

“…Here, we report that the silencing and pharmacological inhibition of PSMD14 induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the dilations of the endoplasmic reticulum (ER) and mitochondria [ 14 , 15 ], in various breast cancer cells but not in the MCF-10A human breast epithelial cell line. Although we need to unravel the critical molecules involved in paraptosis, the underlying mechanisms of paraptosis reportedly include disruption of proteostasis due to proteasomal inhibition [ 14 , 15 , 16 , 17 ] or perturbation of sulfhydryl homeostasis [ 18 , 19 , 20 ], ion (Ca 2+ or K + ) imbalance [ 21 , 22 ], and generation of reactive oxygen species (ROS) [ 23 , 24 , 25 ]. In addition, paraptosis requires de novo protein synthesis [ 14 , 26 ].…”