Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of αVβ3-expressing endothelial cells

A. Borgne-Sanchez, S. Dupont, A. Langonné, L. Baux, H. Lecoeur, D. Chauvier, M. Lassalle, O. Déas, J. J. Brière, M. Brabant, P. Roux, C. Péchoux, J. P. Briand, J. Hoebeke, A. Deniaud, C. Brenner, P. Rustin, L. Edelman, D. Rebouillat, E. Jacotot

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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Résumé

The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed αVβ3 integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (ΔΨm), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.

langue originaleAnglais
Pages (de - à)422-435
Nombre de pages14
journalCell Death and Differentiation
Volume14
Numéro de publication3
Les DOIs
étatPublié - 1 janv. 2007
Modification externeOui

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