1. Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.
- Author
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Borgne-Sanchez A, Dupont S, Langonné A, Baux L, Lecoeur H, Chauvier D, Lassalle M, Déas O, Brière JJ, Brabant M, Roux P, Péchoux C, Briand JP, Hoebeke J, Deniaud A, Brenner C, Rustin P, Edelman L, Rebouillat D, and Jacotot E
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, Cell Survival, Dose-Response Relationship, Drug, Endothelial Cells metabolism, Gene Products, vpr pharmacology, Humans, Lysosomes metabolism, Mice, Mice, Inbred BALB C, Mitochondrial Membranes metabolism, Molecular Sequence Data, Peptides pharmacology, Permeability, Endothelial Cells physiology, Gene Products, vpr pharmacokinetics, Integrin alphaVbeta3 metabolism, Mitochondria metabolism, Peptides pharmacokinetics
- Abstract
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 alpha(V)beta(3) 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 (DeltaPsi(m)), 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.
- Published
- 2007
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