Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
| Autor: | Jacob Westman, Aleksandra Mandic Havelka, Mélanie Beaujouin, Rolf Larsson, Stig Linder, Maria Berndtsson, Emmanuelle Liaudet-Coopman, Linda Rickardson |
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| Rok vydání: | 2009 |
| Předmět: |
Proteasome Endopeptidase Complex
Cancer Research Programmed cell death Cathepsin D Apoptosis Cysteine Proteinase Inhibitors Biology Cathepsin B Membrane Potentials Ubiquitin Cell Line Tumor Lysosome medicine Humans Cathepsin Intracellular Membranes Mitochondria medicine.anatomical_structure Oncology Proteasome Cancer research biology.protein Proteasome inhibitor K562 Cells Lysosomes Proteasome Inhibitors medicine.drug |
| Zdroj: | International Journal of Cancer. 124:1463-1469 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.24004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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