TY - JOUR
T1 - Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of αVβ3-expressing endothelial cells
AU - Borgne-Sanchez, A.
AU - Dupont, S.
AU - Langonné, A.
AU - Baux, L.
AU - Lecoeur, H.
AU - Chauvier, D.
AU - Lassalle, M.
AU - Déas, O.
AU - Brière, J. J.
AU - Brabant, M.
AU - Roux, P.
AU - Péchoux, C.
AU - Briand, J. P.
AU - Hoebeke, J.
AU - Deniaud, A.
AU - Brenner, C.
AU - Rustin, P.
AU - Edelman, L.
AU - Rebouillat, D.
AU - Jacotot, E.
N1 - Funding Information:
Acknowledgements. We thank Dr Sylviane Muller for her critical reading of the manuscript and Dr Naoufal Zamzami for helpful suggestions. We are grateful to Dr Peter Daniel for kindly providing Bax ( + /−) and Bax/Bak (−/−) colon cancer cells generated by Professor B Vogelstein (Johns Hopkins University) and Professor G Chinnadurai (Saint Louis University School of Medicine). This work was supported by grants from the French Ministry of Research (GenHomme Programs 2001 and 2003) to CB (No 01H0480 and No 03L297) and EJ (No 01H0476 and No 03L292), by Agence Nationale pour la Valorisation de la Recherche (ANVAR) to EJ (No R0209333Q and No A0404096Q), by the Association Franc¸aise contre les Myopathies (AFM) to PR, and by Centre National de la Recherche Scientifique (CNRS) and Institut National de la Santé et de la Recherche Médical to PR. DR was supported by ANVAR (No K0109377Q), AL by Centre Régional d’Innovation et de Transfert de Technologie (CRITT) d’Ile de France.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33847053562&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4402018
DO - 10.1038/sj.cdd.4402018
M3 - Article
C2 - 16888644
AN - SCOPUS:33847053562
SN - 1350-9047
VL - 14
SP - 422
EP - 435
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 3
ER -