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Carcinogenesis Advance Access published online on June 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn147
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cathepsin D Protects Human Neuroblastoma Cells from Doxorubicin-Induced Cell Death

Vitalia Sagulenko, Daniel Muth, Evgeny Sagulenko, Tobias Paffhausen, Manfred Schwab and Frank Westermann*

Department of Tumor Genetics B030, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

* To whom correspondence should be addressed: E-mail: f.westermann{at}dkfz.de, Tel: +49 6221-423275, Fax: +49 6221-423277

High incidence of chemotherapy resistance is the primary cause of treatment failure in a subset of neuroblastomas with amplified MYCN. We have previously reported that ectopic MYCN expression promotes proliferation of neuroblastoma Tet21N cells, and simultaneously sensitizes them to the drug-induced apoptosis. In search for genes that are involved in MYCN-dependent regulation of drug resistance, we used a function-based gene cloning approach, and identified CTSD, encoding for a lysosomal aspartyl protease cathepsin D. Downregulation of cathepsin D expression by RNA-interference or inhibition of its enzymatic activity increased sensitivity of MYCN-expressing Tet21N cells to doxorubicin. Overexpression of cathepsin D in Tet21N cells attenuated doxorubicin-induced apoptosis. It was accompanied by activation of Akt and persistent anti-apoptotic activity of Bcl-2. In primary neuroblastomas, high CTSD mRNA levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation (ChIP) and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression. We further show that neuroblastoma cells can secrete mitogenic procathepsin D, and that MYCN expression and especially doxorubicin treatment promote procathepsin D secretion. Extracellular exogenous cathepsin D induces Akt-1 phosphorylation and doxorubicin resistance in sensitive cells. These results demonstrate an important role of cathepsin D in antiapoptotic signaling in neuroblastoma cells and suggest a novel mechanism for the development of chemotherapy resistance in neuroblastoma.

Key Words: MYCN • apoptosis • drug resistance • CTSD

Received January 17, 2008; revised May 16, 2008; accepted June 13, 2008.


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