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Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin‐proteasome system
Author(s) -
Berndtsson Maria,
Beaujouin Melanie,
Rickardson Linda,
Havelka Aleksandra Mandic,
Larsson Rolf,
Westman Jacob,
LiaudetCoopman Emmanuelle,
Linder Stig
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24004
Subject(s) - cathepsin , apoptosis , proteasome , cathepsin d , microbiology and biotechnology , ubiquitin , cathepsin l , cathepsin b , biology , cathepsin s , lysosome , chemistry , biochemistry , enzyme , gene
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.