title: The oncolytic compound LTX-401 targets the Golgi apparatus.
abstract: LTX-401 is an oncolytic amino acid derivative with potential immunogenic properties. Here, we demonstrate that LTX-401 selectively destroys the structure of the Golgi apparatus, as determined by means of ultrastructural analyses and fluorescence microscopic observation of cells expressing Golgi-targeted GFP reporters. Subcellular fractionation followed by mass spectrometric detection revealed that LTX-401 selectively enriched in the Golgi rather than in mitochondria or in the cytosol. The Golgi-dissociating agent Brefeldin A (BFA) reduced cell killing by LTX-401 as it partially inhibited LTX-401-induced mitochondrial release of cytochrome c and the activation of BAX. The cytotoxic effect of LTX-401 was attenuated by the double knockout of BAX and BAK, as well as the mitophagy-enforced depletion of mitochondria, yet was refractory to caspase inhibition. LTX-401 induced all major hallmarks of immunogenic cell death detectable with biosensor cell lines including calreticulin exposure, ATP release, HMGB1 exodus and a type-1 interferon response. Moreover, LTX-401-treated tumors manifested a strong lymphoid infiltration. Altogether these results support the contention that LTX-401 can stimulate immunogenic cell death through a pathway in which Golgi-localized LTX-401 operates upstream of mitochondrial membrane permeabilization.
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.
authors: Heng
authors: H
authors: Zhou
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Allan
authors: A
authors: Sauvat
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|Chemistry Department, University of Coimbra, Coimbra 3004-535, Portugal.
authors: Lígia C
authors: LC
authors: Gomes-da-Silva
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Sylvère
authors: S
authors: Durand
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Sabrina
authors: S
authors: Forveille
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Kristina
authors: K
authors: Iribarren
authors: University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.|Department of Immuno-Oncology, Institut de Cancérologie Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif 94805, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
authors: Takahiro
authors: T
authors: Yamazaki
authors: Gustave Roussy Comprehensive Cancer Center, Villejuif, France CNRS, UMR9196, Villejuif, France.
authors: Sylvie
authors: S
authors: Souquere
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.
authors: Lucillia
authors: L
authors: Bezu
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.
authors: Kevin
authors: K
authors: Müller
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Marion
authors: M
authors: Leduc
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.
authors: Peng
authors: P
authors: Liu
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.
authors: Liwei
authors: L
authors: Zhao
authors: Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.
authors: Aurélien
authors: A
authors: Marabelle
authors: University of Paris Sud XI, Le Kremlin-Bicêtre 94276, France.|Department of Immuno-Oncology, Institut de Cancérologie Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif 94805, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
authors: Laurence
authors: L
authors: Zitvogel
authors: Lytix Biopharma AS, Oslo 0349, Norway.|Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway.
authors: Øystein
authors: Ø
authors: Rekdal
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.
authors: Oliver
authors: O
authors: Kepp
authors: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris 75006, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris 75006, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France.|Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
authors: Guido
authors: G
authors: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D013347:Subcellular Fractions / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C000609766:LTX-315; C000609215:LTX-401; D009842:Oligopeptides; D015091:beta-Alanine; D020126:Brefeldin A