Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Berberine / metabolism
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Berberine / pharmacology*
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Blotting, Western
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Cell Line, Tumor
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Cell Survival / drug effects
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Co-Repressor Proteins
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Models, Biological
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Molecular Chaperones
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Binding / drug effects
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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CDKN1A protein, human
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Co-Repressor Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DAXX protein, human
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Molecular Chaperones
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Berberine
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Doxorubicin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2