Cadmium overkill: autophagy, apoptosis and necrosis signalling in endothelial cells exposed to cadmium.

Barbara Messner,Christian Ploner,David Bernhard,Adrian Türkcan,Günther Laufer

doi:10.1007/s00018-015-2094-9

Barbara Messner, Christian Ploner + Show 3 more

Open Access

https://doi.org/10.1007/s00018-015-2094-9

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Abstract

Apoptosis, necrosis, or autophagy—it is the mode of cell demise that defines the response of surrounding cells and organs. In case of one of the most toxic substances known to date, cadmium (Cd), and despite a large number of studies, the mode of cell death induced is still unclear. As there exists conflicting data as to which cell death mode is induced by Cd both across various cell types and within a single one, we chose to analyse Cd-induced cell death in primary human endothelial cells by investigating all possibilities that a cell faces in undergoing cell death. Our results indicate that Cd-induced death signalling starts with the causation of DNA damage and a cytosolic calcium flux. These two events lead to an apoptosis signalling-related mitochondrial membrane depolarisation and a classical DNA damage response. Simultaneously, autophagy signalling such as ER stress and phagosome formation is initiated. Importantly, we also observed lysosomal membrane permeabilization. It is the integration of all signals that results in DNA degradation and a disruption of the plasma membrane. Our data thus suggest that Cd causes the activation of multiple death signals in parallel. The genotype (for example, p53 positive or negative) as well as other factors may determine the initiation and rate of individual death signals. Differences in the signal mix and speed may explain the differing results recorded as to the Cd-induced mode of cell death thus far. In human endothelial cells it is the sum of most if not all of these signals that determine the mode of Cd-induced cell death: programmed necrosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-2094-9) contains supplementary material, which is available to authorized users.

Highlights

Cadmium (Cd) is a toxic heavy metal and pollutant which is ubiquitously distributed in our environment
The process of Cd-induced endothelial cell death becomes further complicated still, as we have shown that Cd triggers a programmed form of necrotic cell death accomplished by the rupture of lysosomes [43]
The involvement of the Ca2? sensitive non-lysosomal cysteine protease calpain was analysed by the usage of the calpain I and II inhibitor (MDL 28170) showing a significant inhibition of Ca2? flux in cells treated with 15 lM Cd, but no effect in cells treated with 30 lM Cd after 24 h (Fig. 2b)

Summary

Introduction

Cadmium (Cd) is a toxic heavy metal and pollutant which is ubiquitously distributed in our environment. In general and based upon knowledge gained far cell death may be classified into apoptosis, necrosis and autophagy, whereby, above all, detailed molecular and biochemical analyses are indicative of an alternative classification. In this regard, the morphological system of classification is being replaced by a functional system based on the demonstration of detailed signalling pathways and involved molecules [9]. Further adding to the complexity of signalling pathways in response to Cd toxicity, outcome is dependent on Cd concentration; this may serve to explain some of the contradictory reports presently existing as to Cd-induced cell death. Lemaire et al has reported caspase independent Cd-induced cell death in liver cells [21], whereas within the same cells, Oh et al and Lasfer et al provided evidence of caspase-dependent apoptotic signals [22, 23]

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