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Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL

Oncogene volume 21, pages 1963–1977 (2002)Cite this article

Abstract

Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-XL, yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-XL failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-XL.

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Abbreviations

AIF:

apoptosis-inducing factor

ANT:

adenine nucleotide translocator

Atre:

etroctyloside

BA:

bongkrekic acid

COX:

cytochrome c oxidase

CsA:

cyclosporin A

Cyt c:

cytochrome c

DiOC6(3):

3,3′dihexyloxacarbocyanine iodide

δΨm:

mitochondral transmembrane potential

JC-1:

5,5′,6,6′-tetrachloro-1,1′, 3,3′-tetraethylbenzinidazolylcarbocyanine iodide

MMP:

mitochondrial membrane permeabilization

4-MU:

4-methylumbelliferone

4-MUP:

4-methylumbelliferylphosphate

PI:

propidium iodide

Rh123:

rhodamine 123

STS:

staurosporin

VDAC:

voltage-dependant anion channel

vMIA:

viral mitochondrial inhibitor of apoptosis

Vpr:

virel protien R

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Acknowledgements

We thank Dr John C Reed (the Burnham Institute, La Jolla, CA, USA) for recombinant Bax protein and Didier Métivier for technical assistance. This work has been supported by a special grant from the Ligue Nationale contre le Cancer, as well as grants from ANRS (to G Kroemer), ARC (to C Brenner), FRM (to G Kroemer and C Brenner), French Ministry of Sciences (to C Brenner), and the European Commission (QLG1-CT-1999-00739 to G Kroemer). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnologia PRAXIS XXI, Portugal; P Boya from the European Commission (MCFI-2000-00943), I Cohen and D Haouzi from the Ligue Nationale contre le Cancer, CE Hamel from the Comité Val de Marne de la Ligue contre le Cancer, A-S Belzacq from FRM.

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Authors and Affiliations

  1. Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France

    Helena LA Vieira, Patricia Boya, Isabelle Cohen, Chahrazed El Hamel, Delphine Haouzi, Catherine Brenner & Guido Kroemer

  2. Unité de Pharmacochimie Moléculaire et Structurale, INSERM U266 – CNRS UMR860, Université René Descartes (Paris V), F-75005, Paris, France

    Sabine Druillenec & Bernard Roques

  3. CNRS-UMR6022, Université de Technologie de Compiègne, BP 20529, F-60205 Compiègne, France

    Anne-Sophie Belzacq & Catherine Brenner

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Correspondence to Guido Kroemer.

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Vieira, H., Boya, P., Cohen, I. et al. Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL. Oncogene 21, 1963–1977 (2002). https://doi.org/10.1038/sj.onc.1205270

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