title: Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia.
abstract: Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S). By interacting with nicotinamide phosphoribosyltransferase (NAMPT), a protein involved in NAD biosynthesis, PCNA coordinates glycolysis and survival, especially in HL-60R cells. These cells showed a dramatic increase in intracellular NAD+ concentration as well as glycolysis including increased expression and activity of hexokinase 1 and increased lactate production. Furthermore, this functional activity of cytoplasmic PCNA was also demonstrated in patients with acute myeloid leukemia (AML). Our data uncover a novel pathway of nuclear export of PCNA that drives cell survival by increasing metabolism flux.
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Center of Excellence, Labex Inflamex, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Ohayon
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Center of Excellence, Labex Inflamex, France.
authors.forename: Alessia
authors.initials: A
authors.lastname: De Chiara
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Hematology Department, Cochin Hospital, Assistance publique-Hôpitaux de Paris (APHP), Paris, France.|FILO: French Innovative Leukemia Organization (GOELAMS), CHU Bretonneau, TOURS France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Center of Excellence, Labex Inflamex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Candalh
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Center of Excellence, Labex Inflamex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Mocek
authors.affiliation: Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|Biotherapy Department, Necker Hospital, Paris, France.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|FILO: French Innovative Leukemia Organization (GOELAMS), CHU Bretonneau, TOURS France.
authors.forename: Lamya
authors.initials: L
authors.lastname: Haddaoui
authors.affiliation: FILO: French Innovative Leukemia Organization (GOELAMS), CHU Bretonneau, TOURS France.|Hematology Department CHU &UMR INSERM U892/CNRS6299, Université d'Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|Hematology Department, Necker Hospital Assistance publique-Hôpitaux de Paris (APHP), France.|INSERM UMR1163, CNRS ERL 8254, Institut Imagine, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: Institut de Biologie Structurale, Centre Etude Atomique, Grenoble, France.|Université Grenoble Alpes, CNRS, UMR 5075, Grenoble, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Frachet
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Hematology Department, Cochin Hospital, Assistance publique-Hôpitaux de Paris (APHP), Paris, France.|FILO: French Innovative Leukemia Organization (GOELAMS), CHU Bretonneau, TOURS France.
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.|CNRS UMR 8104, Paris, France.|Center of Excellence, Labex Inflamex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
mesh_terms: D000818:Animals; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism*; D004261:DNA Replication; D003630:Daunorubicin / Q000627:therapeutic use; D004351:Drug Resistance; D006019:Glycolysis; D018922:HL-60 Cells; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D054409:Nicotinamide Phosphoribosyltransferase; C472074:HK1 protein, human; D006593:Hexokinase; D003630:Daunorubicin