title: Essential role of Notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles.
abstract: We previously reported that exosomal nanoparticles secreted by human pancreatic tumoral cell lines decrease tumoral cell proliferation through the mitochondria-dependent apoptotic pathway, because of activation of pro-apoptotic phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and of glucose synthase kinase-3beta (GSK-3beta). Interactions between exosomal nanoparticles and cells are thought to involve membrane lipid rafts. However, the underlying mechanism is unknown. Here, we report that the interaction of exosomal nanoparticles with pancreatic cancer cells led to decreased expression of hairy and enhancer-of-split homolog-1 (Hes-1), the intranuclear target of Notch-1 signaling pathway, and to activation of the apoptotic pathway after a cell cycle arrest in G(0)G(1) phase. Strikingly, the expression level of Notch-1 pathway components was critical, because exosomal nanoparticles decreased the proliferation of cells in which these partners are either weakly represented, in differentiated adenocarcinoma cells, or inhibited, in poorly differentiated carcinoma cells, by blocking presenilin in the gamma-secretase complex that regulates the Notch-1 pathway. Overexpression of Notch-1 intracellular domain resulted in the reversion of the cell proliferation inhibition promoted by exosomal nanoparticles. Blocking presenilin unexpectedly resulted in activation of PTEN and GSK-3beta. Conversely, inhibiting either PTEN or GSK-3beta increased Hes-1 expression and partially counteracted the inhibition of proliferation promoted by exosomal nanoparticles, highlighting reciprocal regulations between Notch signaling and PTEN/GSK-3beta. We concluded that interactions of exosomal nanoparticles with target cells, at lipid rafts where Notch-1 pathway partners are localized, hampered the functioning of the Notch-1 survival pathway and activated the apoptotic pathway, which determines tumoral cell fate.
authors.affiliation: INSERM UMR CRO, Aix-Marseille Université, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ristorcelli
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beraud
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mathieu
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
authors.forename: Alain
authors.initials: A
authors.lastname: Verine
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004151:Dipeptides / Q000494:pharmacology; D055354:Exosomes / Q000378:metabolism*; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D053758:Nanoparticles; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D002219:Carbamates; D053148:Caspase 3; D004151:Dipeptides; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins; D051059:PTEN Phosphohydrolase; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C410009:L 685458; C078493:HES1 protein, human; C000605506:GSK3B protein, human; C494929:PTEN protein, human