A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice Export

@article{citeulike:5625738, abstract = {Abstract\ \ Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (ΔΨm). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with ΔΨm loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.}, author = {Brabant, Magali and Baux, Ludwig and Casimir, Richard and Briand, Jean and Chaloin, Olivier and Porceddu, Mathieu and Buron, Nelly and Chauvier, David and Lassalle, Myriam and Lecoeur, Herv\'{e} and Langonn\'{e}, Alain and Dupont, Sylvie and D\'{e}as, Olivier and Brenner, Catherine and Rebouillat, Dominique and Muller, Sylviane and Borgne-Sanchez, Annie and Jacotot, Etienne}, citeulike-article-id = {5625738}, citeulike-linkout-0 = {http://dx.doi.org/10.1007/s10495-009-0394-y}, citeulike-linkout-1 = {http://www.springerlink.com/content/d40w238335022u67}, doi = {10.1007/s10495-009-0394-y}, journal = {Apoptosis}, keywords = {braban09pdf, cells, death, disruption, flavivirus, m, membrane, mitochondrial, protein}, posted-at = {2009-08-25 02:17:32}, priority = {2}, title = {A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice}, url = {http://dx.doi.org/10.1007/s10495-009-0394-y} }

TY - JOUR ID - citeulike:5625738 L3 - citeulike-article-id:5625738 N2 - Abstract  Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (ΔΨm). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with ΔΨm loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds. JF - Apoptosis TI - A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice KW - braban09pdf KW - cells KW - death KW - disruption KW - flavivirus KW - m KW - membrane KW - mitochondrial KW - protein AU - Brabant, Magali AU - Baux, Ludwig AU - Casimir, Richard AU - Briand, Jean AU - Chaloin, Olivier AU - Porceddu, Mathieu AU - Buron, Nelly AU - Chauvier, David AU - Lassalle, Myriam AU - Lecoeur, Hervé AU - Langonné, Alain AU - Dupont, Sylvie AU - Déas, Olivier AU - Brenner, Catherine AU - Rebouillat, Dominique AU - Muller, Sylviane AU - Borgne-Sanchez, Annie AU - Jacotot, Etienne UR - http://dx.doi.org/10.1007/s10495-009-0394-y ER -