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High incidence of chemotherapy resistance is the primary cause of treatment failure in a subset of neuroblastomas with amplifiedMYCN. We have reported previously that ectopicMYCNexpression promotes proliferation of neuroblastoma Tet21N cells and simultaneously sensitizes them to the drug-induced apoptosis. In search for genes that are involved inMYCN-dependent regulation of drug resistance, we used a function-based gene cloning approach and identifiedCTSDencoding for a lysosomal aspartyl protease cathepsin D. Downregulation of cathepsin D expression by RNA interference or inhibition of its enzymatic activity increased sensitivity ofMYCN-expressing Tet21N cells to doxorubicin. Overexpression of cathepsin D in Tet21N cells attenuated doxorubicin-induced apoptosis. It was accompanied by activation of protein kinase B (Akt) and persistent antiapoptotic activity of Bcl-2. In primary neuroblastomas, highCTSDmessenger RNA (mRNA) levels were associated with amplifiedMYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to theCTSDpromoter and activates its transcription, suggesting a direct link between deregulatedMYCNandCTSDmRNA expression. We further show that neuroblastoma cells can secrete mitogenic procathepsin D and thatMYCNexpression 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.

Cathepsin D protects human neuroblastoma cells from doxorubicin-induced cell death