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Abstract
Bcl-2 homologues (such as Bcl-xL) promote survival in part through sequestration of “activator” BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-xL is a prerequisite for small molecules to antagonize Bcl-xL and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-xL attest that displacement of Bax from Bcl-xL is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-xL interactions without affecting Puma/Bcl-xL interactions. In cell-free assays, binding of inactive Bax to Bcl-xL, followed by its displacement from Bcl-xL by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-xL, and it uses Bax-binding Bcl-xL to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-xL inhibitor, ABT-737, when Bcl-xL is present. Thus, the interaction of Bcl-xL with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-xL triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-xL inhibitors.
ACKNOWLEDGMENTS
We feel indebted to Muriel Priault for her generous sharing of reagents and for her advice. We thank David Huang for the gift of wild-type and Bcl-xL knockout MEFs and Jean Claude Martinou for His-tagged recombinant proteins. We thank Lisa Oliver for fruitful comments.
P.J. is supported by ARC (no. 4895), Fondation de France (Tumor Committee), Région Pays de la Loire (CIMATH network), and Institut de Recherche Servier.