Doxorubicin-induced cell death requires cathepsin B in HeLa cells.

Bien, S. and Rimmbach, C. and Neumann, H. and Niessen, J. and Reimer, E. and Ritter, Christoph A and Rosskopf, D. and Cinatl, J. and Michaelis, Martin and Schroeder, H. W. S. and Kroemer, H. K. (2010) Doxorubicin-induced cell death requires cathepsin B in HeLa cells. Biochemical Pharmacology, 80 (10). pp. 1466-77. ISSN 0006-2952. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Abstract

The cysteine protease cathepsin B acts as a key player in apoptosis. Cathepsin B-mediated cell death is induced by various stimuli such as ischemia, bile acids or TNFα. Whether cathepsin B can be influenced by anticancer drugs, however, has not been studied in detail. Here, we describe the modulation of doxorubicin-induced cell death by silencing of cathepsin B expression. Previously, it was shown that doxorubicin, in contrast to other drugs, selectively regulates expression and activity of cathepsin B. Selective silencing of cathepsin B by siRNA or the cathepsin B specific inhibitor CA074Me modified doxorubicin-mediated cell death in Hela tumor cells. Both Caspase 3 activation and PARP cleavage were significantly reduced in cells lacking cathepsin B. Moreover, mitochondrial membrane permeabilization as well as the release of cytochrome C and AIF from mitochondria into cytosol induced by doxorubicin were significantly diminished in cathepsin B suppressed cells. In addition, doxorubicin associated down-regulation of XIAP was not observed in cathepsin B silenced cells. Lack of cathepsin B significantly modified cell cycle regulatory proteins such as cdk1, Wee1 and p21 without significant changes in G(1), S or G(2)M cell cycle phases maybe indicating further cell cycle independent actions of these proteins. Consequently, cell viability following doxorubicin was significantly elevated in cells with cathepsin B silencing. In summary, our data strongly suggest a role of cathepsin B in doxorubicin-induced cell death. Therefore, increased expression of cathepsin B in various types of cancer can modify susceptibility towards doxorubicin.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 05 Jun 2013 17:37 UTC
Last Modified: 17 Jul 2014 09:31 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34066 (The current URI for this page, for reference purposes)
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