title: The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria.
abstract: Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca(2+) signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca(2+) transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca(2+) uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.
authors.affiliation: Inserm ER440-Oncogenesis, Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Centre Eugène Marquis, Inserm ERL440-OSS, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Université de Rennes-1, 2 Avenue du Prof. Léon Bernard, Rennes 35043, France.
authors.forename: A
authors.initials: A
authors.lastname: Fouqué
authors.affiliation: Inserm ER440-Oncogenesis, Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Centre Eugène Marquis, Inserm ERL440-OSS, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Université de Rennes-1, 2 Avenue du Prof. Léon Bernard, Rennes 35043, France.|Laboratoire Commun, OncoTrial UMS Biosit/Biotrial 7-9 Rue Jean-Louis Bertrand, Rennes 35000, France.
authors.forename: E
authors.initials: E
authors.lastname: Lepvrier
authors.affiliation: Inserm ER440-Oncogenesis, Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Centre Eugène Marquis, Inserm ERL440-OSS, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Université de Rennes-1, 2 Avenue du Prof. Léon Bernard, Rennes 35043, France.
authors.forename: L
authors.initials: L
authors.lastname: Debure
authors.affiliation: Inserm U1060, CarMeN, Université Claude Bernard Lyon 1, 8 Avenue Rockfeller, Lyon 69373, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Gouriou
authors.affiliation: Inserm ER440-Oncogenesis, Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Centre Eugène Marquis, Inserm ERL440-OSS, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Université de Rennes-1, 2 Avenue du Prof. Léon Bernard, Rennes 35043, France.|Laboratoire Commun, OncoTrial UMS Biosit/Biotrial 7-9 Rue Jean-Louis Bertrand, Rennes 35000, France.
authors.forename: M
authors.initials: M
authors.lastname: Malleter
authors.affiliation: Université de Bordeaux, 146 Rue Léo Saignat, Bordeaux 33076, France.|Inserm U1218, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: V
authors.initials: V
authors.lastname: Delcroix
authors.affiliation: Inserm U1060, CarMeN, Université Claude Bernard Lyon 1, 8 Avenue Rockfeller, Lyon 69373, France.|Hospices Civils de Lyon, Hôpital Louis Pradel, Services D'explorations Fonctionnelles Cardiovasculaires et CIC de Lyon, Lyon 69394, France.
authors.forename: M
authors.initials: M
authors.lastname: Ovize
authors.affiliation: Université de Bordeaux, 146 Rue Léo Saignat, Bordeaux 33076, France.|Inserm U1045, Centre de Recherche Cardiothoracique de Bordeaux, 146 Rue Léo Saignat, Bordeaux 33076, France.
authors.forename: T
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Molecular Targets Group, James Graham Brown Cancer Center, Departments of Medicine, and Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Université de Bordeaux, 146 Rue Léo Saignat, Bordeaux 33076, France.|Inserm U1218, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: M
authors.initials: M
authors.lastname: Hammadi
authors.affiliation: Université de Bordeaux, 146 Rue Léo Saignat, Bordeaux 33076, France.|Inserm U1218, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: P
authors.initials: P
authors.lastname: Vacher
authors.affiliation: Inserm ER440-Oncogenesis, Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Centre Eugène Marquis, Inserm ERL440-OSS, Rue Bataille Flandres Dunkerque, Rennes 35042, France.|Université de Rennes-1, 2 Avenue du Prof. Léon Bernard, Rennes 35043, France.
authors.forename: P
authors.initials: P
authors.lastname: Legembre
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002465:Cell Movement; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D015220:Calcium Channels; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor; C034703:mitochondrial calcium uniporter; D050995:Voltage-Dependent Anion Channel 1; D002118:Calcium