Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.
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.
Borgne-Sanchez
A
A
Theraptosis Research Laboratory, THERAPTOSIS S.A., 28 rue du Dr. Roux, Paris cedex 15, France.
Dupont
S
S
Langonné
A
A
Baux
L
L
Lecoeur
H
H
Chauvier
D
D
Lassalle
M
M
Déas
O
O
Brière
J-J
JJ
Brabant
M
M
Roux
P
P
Péchoux
C
C
Briand
J-P
JP
Hoebeke
J
J
Deniaud
A
A
Brenner
C
C
Rustin
P
P
Edelman
L
L
Rebouillat
D
D
Jacotot
E
E
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D016336:Gene Products, vpr / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D010539:Permeability
D016336:Gene Products, vpr; D039302:Integrin alphaVbeta3; D010455:Peptides