Abstract
Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs and their activation of Bax are not inhibited but rather potentiated by Bcl-2. NuBCP-9 and its enantiomer bind to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. NuBCP-9s act as molecular switches to dislodge the Bcl-2 BH4 domain, exposing its BH3 domain, which in turn blocks the activity of antiapoptotic Bcl-X(L).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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BH3 Interacting Domain Death Agonist Protein / metabolism
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Binding Sites
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Drug
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Female
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HeLa Cells
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Humans
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Jurkat Cells
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Mice
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Mice, Knockout
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Mice, SCID
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Neoplasms, Experimental / drug therapy*
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Oligopeptides / chemistry
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Oligopeptides / pharmacology*
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Peptide Fragments / pharmacology
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Protein Binding
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Protein Conformation
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism*
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Stereoisomerism
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Time Factors
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Transfection
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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BH3 Interacting Domain Death Agonist Protein
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Bax protein (53-86)
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DNA-Binding Proteins
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NR4A1 protein, human
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Oligopeptides
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Steroid
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bcl-2-Associated X Protein
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bcl-X Protein