BH3 Mimetics Demonstrate Differential Activities Dependent Upon the Functional Repertoire of Pro- and Anti-Apoptotic BCL-2 Family Proteins [Signal Transduction]

August 5th, 2014 by Renault, T. T., Elkholi, R., Bharti, A., Chipuk, J. E.

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 pro-apoptotic 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 if 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 rationally designed. 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 (LUV) model systems that faithfully recapitulate BAX-dependent MOMP. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to de-repress pro-apoptotic 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 while the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by pro-apoptotic BCL-2 proteins.
  • Posted in Journal of Biological Chemistry, Publications
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