The Journal of biological chemistry, 2014-09, Vol.289 (38), p.26481-26491
2014
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- Autor(en) / Beteiligte
- Titel
- B Cell Lymphoma-2 (BCL-2) Homology Domain 3 (BH3) Mimetics Demonstrate Differential Activities Dependent upon the Functional Repertoire of Pro- and Anti-apoptotic BCL-2 Family Proteins
- Ist Teil von
- The Journal of biological chemistry, 2014-09, Vol.289 (38), p.26481-26491
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The B cell lymphoma-2 (BCL-2) family is the key mediator of cellular sensitivity to apoptosis during pharmacological interventions for numerous human pathologies, including cancer. There is tremendous interest to understand how the proapoptotic BCL-2 effector members (e.g. BCL-2-associated X protein, BAX) cooperate with the BCL-2 homology domain only (BH3-only) subclass (e.g. BCL-2 interacting mediator of death, BIM; BCL-2 interacting-domain death agonist, BID) to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis and whether these mechanisms may be pharmacologically exploited to enhance the killing of cancer cells. Indeed, small molecule inhibitors of the anti-apoptotic BCL-2 family members have been designed rationally. However, the success of these “BH3 mimetics” in the clinic has been limited, likely due to an incomplete understanding of how these drugs function in the presence of multiple BCL-2 family members. To increase our mechanistic understanding of how BH3 mimetics cooperate with multiple BCL-2 family members in vitro, we directly compared the activity of several BH3-mimetic compounds (i.e. ABT-263, ABT-737, GX15-070, HA14.1, TW-37) in biochemically defined large unilamellar vesicle model systems that faithfully recapitulate BAX-dependent mitochondrial outer membrane permeabilization. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to derepress proapoptotic molecules from anti-apoptotic proteins. Using mitochondria loaded with fluorescent BH3 peptides and cells treated with inducers of cell death, these differences were supported. Together, these data suggest that although the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by proapoptotic BCL-2 proteins.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9258eISSN: 1083-351XDOI: 10.1074/jbc.M114.569632Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4176207
- Format
- –
- Schlagworte
- Aniline Compounds - chemistry, Aniline Compounds - pharmacology, Animals, Apoptosis - drug effects, Apoptosis Regulatory Proteins - chemistry, Apoptosis Regulatory Proteins - physiology, bcl-2-Associated X Protein - chemistry, bcl-2-Associated X Protein - physiology, Bcl-2-Like Protein 11, bcl-X Protein - chemistry, bcl-X Protein - physiology, Benzamides - chemistry, Benzamides - pharmacology, Benzopyrans - chemistry, Benzopyrans - pharmacology, BH3 Interacting Domain Death Agonist Protein - chemistry, BH3 Interacting Domain Death Agonist Protein - physiology, Biphenyl Compounds - chemistry, Biphenyl Compounds - pharmacology, Cell Biology, HeLa Cells, Humans, Membrane Proteins - chemistry, Membrane Proteins - physiology, Mice, Mitochondria, Liver - drug effects, Mitochondria, Liver - metabolism, Mitochondrial Membranes - metabolism, Molecular Mimicry, Myeloid Cell Leukemia Sequence 1 Protein - chemistry, Myeloid Cell Leukemia Sequence 1 Protein - physiology, Nitriles - chemistry, Nitriles - pharmacology, Nitrophenols - chemistry, Nitrophenols - pharmacology, Permeability, Piperazines - chemistry, Piperazines - pharmacology, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins - chemistry, Proto-Oncogene Proteins - physiology, Pyrroles - chemistry, Pyrroles - pharmacology, Sulfonamides - chemistry, Sulfonamides - pharmacology, Sulfones - chemistry, Sulfones - pharmacology, Unilamellar Liposomes - chemistry