Abstract
Peroxidized low-density lipoprotein (p-LDL) has been previously demonstrated to be preferentially cytotoxic to certain malignant cells compared to normal cells of the same type. We present evidence that p-LDL is at least partially taken up through the LDL receptor and that it becomes localized in lysosomes. The integrity of lysosomes of p-LDL-treated cells is compromised, and leakage of their contents into the cytosol occurs. This leakage occurs early and precedes mitochondrial dysfunction. Brefeldin A inhibits this leakage, perhaps by interfering with the traffic between endosomes and lysosomes. Electron micrographs taken at various times suggest a mechanism of cell death which resembles certain aspects of the broad definition of apoptosis. However, we suggest that the cell death observed following p-LDL-induced release of lysosomal contents is essentially unique, with released lysosomal enzymes degrading the cell from within. We suggest that this process should be described as endopepsis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / pathology
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Adenocarcinoma / ultrastructure
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Brefeldin A
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Cell Death / drug effects
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Cell Death / physiology
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Cyclopentanes / pharmacology
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Drug Synergism
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Endopeptidases / physiology*
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Fibrosarcoma / drug therapy
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Fibrosarcoma / pathology
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Fibrosarcoma / ultrastructure
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Hip / pathology
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Humans
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Hydrolases / metabolism
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Kinetics
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Lipoproteins, LDL / antagonists & inhibitors
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Lipoproteins, LDL / pharmacokinetics
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Lipoproteins, LDL / toxicity*
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Lysosomes / enzymology
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Lysosomes / metabolism
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Male
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Mitochondria / drug effects
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Mitochondria / physiology
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology*
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Peroxides / toxicity*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / ultrastructure
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Protein Synthesis Inhibitors / pharmacology
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Receptors, LDL / metabolism
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Tumor Cells, Cultured
Substances
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Cyclopentanes
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Lipoproteins, LDL
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Peroxides
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Protein Synthesis Inhibitors
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Receptors, LDL
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Brefeldin A
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Hydrolases
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Endopeptidases