title: PLA2R1 kills cancer cells by inducing mitochondrial stress.
abstract: Little is known about the biological functions of the phospholipase A2 receptor (PLA2R1) except that it has the ability to bind a few secreted phospholipases A2 (sPLA2's). We have previously shown that PLA2R1 regulates senescence in normal human cells. In this study, we investigated the ability of PLA2R1 to control cancer cell growth. Analysis of expression in cancer cells indicates a marked PLA2R1 decrease in breast cancer cell lines compared to normal or nontransformed human mammary epithelial cells. Accordingly, PLA2R1 ectopic expression in PLA2R1-negative breast cancer cell lines led to apoptosis, whereas a prosenescence response was predominantly triggered in normal cells. PLA2R1 structure-function studies and the use of chemical inhibitors of sPLA2-related signaling pathways suggest that the effect of PLA2R1 is sPLA2-independent. Functional experiments demonstrate that PLA2R1 regulation of cell death is driven by a reactive oxygen species (ROS)-dependent mechanism. While screening for ROS-producing complexes involved in PLA2R1 biological responses, we identified a critical role for the mitochondrial electron transport chain in PLA2R1-induced ROS production and cell death. Taken together, this set of data provides evidence for an important role of PLA2R1 in controlling cancer cell death by influencing mitochondrial biology.
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France; UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2, Lille F-5900, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, CNRS, and Université de Nice-Sophia Antipolis, Valbonne F-06560, France.
authors.forename: Christophe A
authors.initials: CA
authors.lastname: Girard
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Gras
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Bouchet
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.affiliation: UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2, Lille F-5900, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: de Launoit
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Simonnet
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, CNRS, and Université de Nice-Sophia Antipolis, Valbonne F-06560, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France. Electronic address: david.bernard@lyon.unicancer.fr.
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053938:DNA Fragmentation; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D054507:Receptors, Phospholipase A2 / Q000502:physiology*
chemical_list: D045222:Electron Transport Chain Complex Proteins; C516360:PLA2R1 protein, human; D017382:Reactive Oxygen Species; D054507:Receptors, Phospholipase A2
keywords: Cell death; Free radicals; Mitochondria; PLA2R1; ROS; Senescence