| Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways. | |
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MedLine Citation:
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PMID: 20595817 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Multiple myeloma (MM) is an incurable plasma cell malignancy in which p53 is rarely mutated. Thus, activation of the p53 pathway by a small molecule inhibitor of the p53-MDM2 interaction, nutlin, in MM cells retaining wild type p53 is an attractive therapeutic strategy. Recently we reported that nutlin plus velcade (a proteasome inhibitor) displayed a synergistic response in MM. However, the mechanism of the p53-mediated apoptosis in MM has not been fully understood. Our data show that nutlin-induced apoptosis correlated with reduction in cell viability, upregulation of p53, p21 and MDM2 protein levels with a simultaneous increase in pro-apoptotic targets PUMA, Bax and Bak and downregulation of anti-apoptotic targets Bcl2 and survivin and activation of caspase in MM cells harboring wild type p53. Nutlin-induced apoptosis was inhibited when activation of caspase was blocked by the caspase inhibitor. Nutlin caused mitochondrial translocation of p53 where it binds with Bcl2, leading to cytochrome C release. Moreover, blocking the transcriptional arm of p53 by the p53-specific transcriptional inhibitor, pifithrin-α, not only inhibited nutlin-induced upregulation of p53-transcriptional targets but also augmented apoptosis in MM cells, suggesting an association of transcription-independent pathway of apoptosis. However, inhibitor of mitochondrial translocation of p53, PFT-μ, did not prevent nutlin-induced apoptosis, suggesting that the p53 transcription-dependent pathway was also operational in nutlin-induced apoptosis in MM. Our study provides the evidence that nutlin-induced apoptosis in MM cells is mediated by transcription-dependent and -independent pathways and supports further clinical evaluation of nutlin as a novel therapeutic agent in MM. |
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Authors:
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Manujendra N Saha; Hua Jiang; Hong Chang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-01 |
Journal Detail:
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Title: Cancer biology & therapy Volume: 10 ISSN: 1555-8576 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-11-18 Completed Date: 2011-04-18 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 567-78 Citation Subset: IM |
Affiliation:
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Division of Molecular and Cellular Biology, Toronto General Hospital Research Institute, Dept of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Apoptosis Regulatory Proteins / genetics, metabolism Benzothiazoles / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism Dose-Response Relationship, Drug Flow Cytometry Gene Expression Profiling Gene Expression Regulation, Neoplastic / drug effects Humans Imidazoles / pharmacology* Immunoblotting Multiple Myeloma / genetics, metabolism, pathology Piperazines / pharmacology* Protein Binding / drug effects Protein Transport / drug effects Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism Proto-Oncogene Proteins c-mdm2 / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Sulfonamides / pharmacology Toluene / analogs & derivatives, pharmacology Transcription, Genetic / drug effects Tumor Suppressor Protein p53 / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/2-phenylacetylenesulfonamide; 0/Apoptosis Regulatory Proteins; 0/Benzothiazoles; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Imidazoles; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 0/pifithrin; 108-88-3/Toluene; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
| Comments/Corrections | |
Comment In:
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Cancer Biol Ther. 2010 Sep;10(6):579-81
[PMID:
20716967
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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