Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin‐proteasome system

The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin‐dependent apoptosis. Using pharmacological inhibitors and siRNA, we i...

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Bibliographic Details
Published in:International journal of cancer 2009-03, Vol.124 (6), p.1463-1469
Main Authors: Berndtsson, Maria, Beaujouin, Melanie, Rickardson, Linda, Havelka, Aleksandra Mandic, Larsson, Rolf, Westman, Jacob, Liaudet‐Coopman, Emmanuelle, Linder, Stig
Format: Article
Language:English
Subjects:
Antineoplastic agents
apoptosis
Apoptosis - physiology
Biological and medical sciences
Cathepsin B - metabolism
cathepsin D
Cathepsin D - metabolism
Cell Line, Tumor
chemical biology
Cysteine Proteinase Inhibitors - therapeutic use
General aspects
Humans
Intracellular Membranes - physiology
K562 Cells - drug effects
Lysosomes - pathology
Medical sciences
MEDICIN
Medicin och hälsovetenskap
MEDICINE
Membrane Potentials - physiology
Mitochondria - physiology
Pharmacology. Drug treatments
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors
Tumors
Ubiquitin - antagonists & inhibitors
ubiquitin isopeptidase
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Summary:The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin‐dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D‐dependent caspase‐cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high‐molecular‐mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin‐D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin‐dependent apoptosis‐inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D‐dependent apoptosis. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
1097-0215
DOI:10.1002/ijc.24004