title: Cadmium overkill: autophagy, apoptosis and necrosis signalling in endothelial cells exposed to cadmium.
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.
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, AKH, Level 8 G9.03, Währinger Gürtel 18-20, 1090, Vienna, Austria. barbara.messner@meduniwien.ac.at.
authors.forename: Barbara
authors.initials: B
authors.lastname: Messner
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, AKH, Level 8 G9.03, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Adrian
authors.initials: A
authors.lastname: Türkcan
authors.affiliation: Plastic, Reconstructive and Aesthetic Surgery Innsbruck, Department of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Ploner
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, AKH, Level 8 G9.03, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Laufer
authors.affiliation: Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002614:Chelating Agents / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004533:Egtazic Acid / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D004533:Egtazic Acid; D002118:Calcium
keywords: Apoptosis; Autophagy; Calcium; Lysosome; Necrosis; p53