| Etoposide induces protein kinase Cdelta- and caspase-3-dependent apoptosis in neuroblastoma cancer cells. | |
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MedLine Citation:
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PMID: 19549763 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In this report, we reveal that etoposide inhibits the proliferation of SK-N-AS neuroblastoma cancer cells and promotes protein kinase Cdelta (PKCdelta)- and caspase-dependent apoptosis. Etoposide induces the caspase-3-dependent cleavage of PKCdelta to its active p40 fragment, and active PKCdelta triggers the processing of caspase-3 by a positive-feedback mechanism. Treatment of cells with the caspase-3-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone or caspase-3-specific small interacting RNA (siRNA) prevented the etoposide-induced activation of caspase-8 and inhibited apoptosis. The silencing of the caspase-2 or caspase-8 genes using siRNAs did not affect the etoposide-induced processing of caspase-3, indicating that these caspases lie downstream of caspase-3 in this signaling pathway. Furthermore, the etoposide-induced processing of caspase-2 required the expression of caspase-8, and the etoposide-mediated processing of caspase-8 required the expression of caspase-2, indicating that these two caspases activate each other after etoposide treatment. We also observed that etoposide-mediated apoptosis was decreased by treating the cells with the caspase-6-specific inhibitor benzyloxycarbonyl-Val-Glu(OMe)-Ile-Asp-(OMe)-fluoromethyl ketone and that caspase-6 was activated by a caspase-8-dependent mechanism. Finally, we show that rottlerin blocks etoposide-induced apoptosis by inhibiting the PKCdelta-mediated activation of caspase-3 and by degrading caspase-2, which prevents caspase-8 activation. Our results add important insights into how etoposide mediates apoptotic signaling and how targeting these pathways may lead to the development of novel therapeutics for the treatment of neuroblastomas. |
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Authors:
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Travis W Day; Ching-Huang Wu; Ahmad R Safa |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-06-23 |
Journal Detail:
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Title: Molecular pharmacology Volume: 76 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-08-24 Completed Date: 2009-09-09 Revised Date: 2010-09-02 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 632-40 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology and Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents, Phytogenic
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pharmacology* Apoptosis* Caspase 3 / metabolism* Cell Line, Tumor Cell Proliferation / drug effects Etoposide / pharmacology* Humans Neuroblastoma / enzymology* Protein Kinase C-delta / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01-CA101743/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Phytogenic; 33419-42-0/Etoposide; EC 2.7.11.13/Protein Kinase C-delta; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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