title: The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs.
abstract: Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France. Electronic address: guillaume.bossis@igmm.cnrs.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bossis
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Chamseddine
authors.initials: C
authors.lastname: Kifagi
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Marko
authors.initials: M
authors.lastname: Ristic
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Vergez
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Tamara
authors.initials: T
authors.lastname: Salem
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
authors.forename: Héléna
authors.initials: H
authors.lastname: Boutzen
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Hayeon
authors.initials: H
authors.lastname: Baik
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Brockly
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
authors.forename: Mireia
authors.initials: M
authors.lastname: Pelegrin
authors.affiliation: Genomics Research Unit, Centre de Recherche Public de la Santé (CRP-Santé) 84, Val Fleuri 1526, Luxembourg.
authors.forename: Tony
authors.initials: T
authors.lastname: Kaoma
authors.affiliation: Genomics Research Unit, Centre de Recherche Public de la Santé (CRP-Santé) 84, Val Fleuri 1526, Luxembourg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France; Département d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, 1 Avenue Irène Joliot-Curie, 31059 Toulouse cedex, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.affiliation: Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
authors.affiliation: Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France. Electronic address: marc.piechaczyk@igmm.cnrs.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Piechaczyk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004195:Disease Models, Animal; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D025842:SUMO-1 Protein; D003561:Cytarabine; D005047:Etoposide; D003630:Daunorubicin