| Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. | |
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MedLine Citation:
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PMID: 20935220 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Berberine, a natural product derived from a plant used in Chinese herbal medicine, is reported to exhibit anticancer effects; however, its mechanism of action is not clearly defined. Herein, we demonstrate that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells by downregulating the MDM2 oncoprotein. The proapoptotic effects of berberine were closely associated with both the MDM2 expression levels and p53 status of a set of ALL cell lines. The most potent apoptosis was induced by berberine in ALL cells with both MDM2 overexpression and a wild-type (wt)-p53, whereas no proapoptotic effect was detected in ALL cells that were negative for MDM2 and wt-p53. In contrast to the conventional chemotherapeutic drug doxorubicin, which induces p53 activation and a subsequent upregulation of MDM2, berberine strongly induced persistent downregulation of MDM2 followed by a steady-state activation of p53. We discovered that downregulation of MDM2 in ALL cells by berberine occurred at a posttranslational level through modulation of death domain-associated protein (DAXX), which disrupted the MDM2-DAXX-HAUSP interactions and thereby promoted MDM2 self-ubiquitination and degradation. Given that MDM2-overexpressing cancer cells are commonly chemoresistant, our findings suggest that this naturally derived agent may have a highly useful role in the treatment of cancer patients with refractory disease. |
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Authors:
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Xiaoling Zhang; Lubing Gu; Jiansha Li; Noopur Shah; Jing He; Lin Yang; Qun Hu; Muxiang Zhou |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-08 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-08 Completed Date: 2011-02-10 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 9895-904 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University School of Medicine, Atlanta, Georgia, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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genetics,
metabolism* Antibiotics, Antineoplastic / pharmacology Apoptosis / drug effects* Apoptosis Regulatory Proteins / genetics, metabolism Berberine / metabolism, pharmacology* Blotting, Western Cell Line, Tumor Cell Survival / drug effects Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism Dose-Response Relationship, Drug Doxorubicin / pharmacology Gene Expression Regulation, Leukemic / drug effects Humans Models, Biological Mutation Nuclear Proteins / genetics, metabolism* Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics, metabolism, pathology Protein Binding / drug effects Protein Processing, Post-Translational / drug effects Proto-Oncogene Proteins / genetics, metabolism Proto-Oncogene Proteins c-mdm2 / genetics, metabolism* RNA Interference Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Protein p53 / genetics, metabolism bcl-2-Associated X Protein / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA123490/CA/NCI NIH HHS; R01 CA123490-04/CA/NCI NIH HHS; R01 CA123490-05/CA/NCI NIH HHS; R01 CA143107/CA/NCI NIH HHS; R01 CA143107-01/CA/NCI NIH HHS; R01 CA143107-02/CA/NCI NIH HHS; R01 CA143107-03/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Antibiotics, Antineoplastic; 0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DAXX protein, human; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 2086-83-1/Berberine; 23214-92-8/Doxorubicin; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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