Intracellular Ca2 + Imbalance Critically Contributes to Paraptosis.

Eunhee Kim,Hong Jae Lee,Dong Min Lee,Kyeong Sook Choi,Min Ji Seo

doi:10.3389/fcell.2020.607844

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.

Highlights

The term “paraptosis” was first introduced to describe a form of programmed cell death displaying cytoplasmic vacuolation consisting in mitochondrial and/or endoplasmic reticulum (ER) dilation (Sperandio et al, 2000)
The activation of mitogen-activated protein (MAP) kinases, such as c-Jun N-terminal protein kinases (JNKs), MAP kinase kinase 2 (MEK-2), and p38, has been found to be positively involved in the paraptosis induced by many natural products or chemicals (Zhang et al, 2009, 2010; Yoon et al, 2010, 2012, 2014; Wang et al, 2012; Yumnam et al, 2014; Hager et al, 2018; Han et al, 2018; Fontana et al, 2019; Yokoi et al, 2020), whereas AIP-1/Alix appears to be negatively involved in some cases of paraptosis (Sperandio et al, 2004; Valamanesh et al, 2007; Yoon et al, 2010, 2014; Han et al, 2018; Xue et al, 2018)
Since paraptosis-inducing agents simultaneously target both the mitochondria and the ER, which are already under stress in cancer cells, therapeutic strategies aimed at inducing paraptosis may offer a two-pronged attack strategy to selectively kill cancer cells

Summary

Introduction

The term “paraptosis” was first introduced to describe a form of programmed cell death displaying cytoplasmic vacuolation consisting in mitochondrial and/or endoplasmic reticulum (ER) dilation (Sperandio et al, 2000).

Results

Conclusion