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Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
Karolinska Institutet.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2009 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 6, 1463-1469 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2009. Vol. 124, no 6, 1463-1469 p.
Keyword [en]
apoptosis, cathepsin D, ubiquitin isopeptidase, chemical biology
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-102351DOI: 10.1002/ijc.24004ISI: 000263539600030PubMedID: 19089926OAI: oai:DiVA.org:uu-102351DiVA: diva2:214755
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2012-03-15Bibliographically approved

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