| Cisplatin-induced apoptosis in melanoma cells: role of caspase-3 and caspase-7 in Apaf-1 proteolytic cleavage and in execution of the degradative phases. | |
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MedLine Citation:
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PMID: 15033720 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis protease-activating factor-1 (Apaf-1), which plays a central role in the formation of the apoptosome, is absent or poorly expressed (because of a transcriptional silencing by methylation) in a substantial percentage of metastatic melanomas and melanoma cell lines, which are unable to activate caspase-9 and execute the mitochondrial pathway of apoptosis. We studied cisplatin-induced apoptosis of the Apaf-1-positive human metastatic Me665/2/21 melanoma cells. Our results indicate that caspase-7 is already processed in still-adhering cells and such activation, contrary to the common view, precedes caspase-3 processing. As expected by the cytochrome c release into the cytosol, caspase-9 is processed to active forms (p37 and p35), along with a yet-unidentified p28. Interestingly, we also demonstrate a remarkable loss of Apaf-1 protein, along with the appearance of a related immunoreactive fragment of approximate, equals 26 kDa; such proteolytic degradation proves to be a caspase-3/-7-mediated event. Our data also indicate that the inhibition afforded by ac-DEVD-CHO on several components (i.e., caspase-3/-7 and caspase-9 activities), and Apaf-1 proteolytic degradation, does not significantly abrogate either the apoptotic morphology or the cleavage of canonical targets, such as poly(ADP-ribose) polymerase (PARP) and lamin B. These results suggest that caspase-3 and caspase-7 are dispensable for the execution of apoptosis and, in our cellular model, the point of no return could be out of the mitochondrial cascade. |
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Authors:
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Barbara Del Bello; Marta A Valentini; Mario Comporti; Emilia Maellaro |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Annals of the New York Academy of Sciences Volume: 1010 ISSN: 0077-8923 ISO Abbreviation: Ann. N. Y. Acad. Sci. Publication Date: 2003 Dec |
Date Detail:
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Created Date: 2004-03-22 Completed Date: 2004-06-15 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7506858 Medline TA: Ann N Y Acad Sci Country: United States |
Other Details:
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Languages: eng Pagination: 200-4 Citation Subset: IM |
Affiliation:
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Department of Pathophysiology and Experimental Medicine, University of Siena, via A. Moro, 53100 Siena, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Apoptotic Protease-Activating Factor 1 Caspase 3 Caspase 7 Caspases / metabolism* Cell Line, Tumor Cisplatin / toxicity* Cysteine Proteinase Inhibitors / pharmacology Humans Melanoma / pathology Neoplasm Metastasis Proteins / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/APAF1 protein, human; 0/Apoptotic Protease-Activating Factor 1; 0/Cysteine Proteinase Inhibitors; 0/Proteins; 15663-27-1/Cisplatin; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP7 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspases |
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