title: The oncolytic peptide LTX-315 kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization.
abstract: LTX-315 has been developed as an amphipathic cationic peptide that kills cancer cells. Here, we investigated the putative involvement of mitochondria in the cytotoxic action of LTX-315. Subcellular fractionation of LTX-315-treated cells, followed by mass spectrometric quantification, revealed that the agent was enriched in mitochondria. LTX-315 caused an immediate arrest of mitochondrial respiration without any major uncoupling effect. Accordingly, LTX-315 disrupted the mitochondrial network, dissipated the mitochondrial inner transmembrane potential, and caused the release of mitochondrial intermembrane proteins into the cytosol. LTX-315 was relatively inefficient in stimulating mitophagy. Cells lacking the two pro-apoptotic multidomain proteins from the BCL-2 family, BAX and BAK, were less susceptible to LTX-315-mediated killing. Moreover, cells engineered to lose their mitochondria (by transfection with Parkin combined with treatment with a protonophore causing mitophagy) were relatively resistant against LTX-315, underscoring the importance of this organelle for LTX-315-mediated cytotoxicity. Altogether, these results support the notion that LTX-315 kills cancer cells by virtue of its capacity to permeabilize mitochondrial membranes.
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Forveille
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Allan
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sica
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Izzo
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Sylvère
authors.initials: S
authors.lastname: Durand
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Müller
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: University of Paris Sud XI, Kremlin Bicêtre, France.|Department of Immuno-Oncology, Institut de Cancérologie Gustave Roussy Cancer Campus, Villejuif, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Lytix Biopharma, Oslo, Norway.|University of Tromsø, Institute of Medical Biology, Tromsø, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rekdal
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D009369:Neoplasms / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C000595707:BCL2 protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C000609766:LTX-315; D009842:Oligopeptides; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: LTX-315; cancer; mitochondrial membrane permeabilization; mitophagy; necrosis