title: Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility.
abstract: Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: V
authors.initials: V
authors.lastname: Edmond
authors.affiliation: INSERM UMR 866, Dijon, France.
authors.forename: F
authors.initials: F
authors.lastname: Dufour
authors.affiliation: 1] INSERM UMR 1037, Toulouse, France [2] Université Toulouse III-Paul Sabatier, Toulouse, France [3] Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: G
authors.initials: G
authors.lastname: Poiroux
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: K
authors.initials: K
authors.lastname: Shoji
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: M
authors.initials: M
authors.lastname: Malleter
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Fouqué
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: S
authors.initials: S
authors.lastname: Tauzin
authors.affiliation: Inserm U1052, CNRS UMR 5286, Université de Lyon, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard Lyon, Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Rimokh
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France.
authors.forename: O
authors.initials: O
authors.lastname: Sergent
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Penna
authors.affiliation: INSERM U1048, Plateau Metatoul Lipidomique, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Dupuy
authors.affiliation: 1] INSERM UMR 1037, Toulouse, France [2] Université Toulouse III-Paul Sabatier, Toulouse, France [3] Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: T
authors.initials: T
authors.lastname: Levade
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France.
authors.forename: N
authors.initials: N
authors.lastname: Theret
authors.affiliation: INSERM UMR 866, Dijon, France.
authors.forename: O
authors.initials: O
authors.lastname: Micheau
authors.affiliation: 1] INSERM UMR 1037, Toulouse, France [2] Université Toulouse III-Paul Sabatier, Toulouse, France [3] Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Ségui
authors.affiliation: 1] Université de Rennes-1, Rennes, France [2] INSERM UMR 1085, IRSET, Rennes, France [3] Equipe Labellisée Ligue Contre Le Cancer, Rennes, France [4] Centre Eugène Marquis, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Legembre
mesh_terms: D002462:Cell Membrane / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008560:Membrane Fluidity / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009369:Neoplasms / Q000473:pathology*; D051049:Sphingosine N-Acyltransferase / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase