title: NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation.
abstract: Ionizing radiation (IR) causes not only acute tissue damage, but also late effects in several cell generations after the initial exposure. The thyroid gland is one of the most sensitive organs to the carcinogenic effects of IR, and we have recently highlighted that an oxidative stress is responsible for the chromosomal rearrangements found in radio-induced papillary thyroid carcinoma. Using both a human thyroid cell line and primary thyrocytes, we investigated the mechanism by which IR induces the generation of reactive oxygen species (ROS) several days after irradiation. We focused on NADPH oxidases, which are specialized ROS-generating enzymes known as NOX/DUOX. Our results show that IR induces delayed NADPH oxidase DUOX1-dependent H2O2 production in a dose-dependent manner, which is sustained for several days. We report that p38 MAPK, activated after IR, increased DUOX1 via IL-13 expression, leading to persistent DNA damage and growth arrest. Pretreatment of cells with catalase, a scavenger of H2O2, or DUOX1 down-regulation by siRNA abrogated IR-induced DNA damage. Analysis of human thyroid tissues showed that DUOX1 is elevated not only in human radio-induced thyroid tumors, but also in sporadic thyroid tumors. Taken together, our data reveal a key role of DUOX1-dependent H2O2 production in long-term persistent radio-induced DNA damage. Our data also show that DUOX1-dependent H2O2 production, which induces DNA double-strand breaks, can cause genomic instability and promote the generation of neoplastic cells through its mutagenic effect.
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; Unité de Biologie et de Recherche Médicale, Centre National de l'Energie, des Sciences et des Techniques Nucléaires, Rabat M-10001, Morocco;
authors.forename: Rabii
authors.initials: R
authors.lastname: Ameziane-El-Hassani
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France;
authors.forename: Monique
authors.initials: M
authors.lastname: Talbot
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France;
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: de Souza Dos Santos
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France;
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.affiliation: Institut Gustave Roussy, Villejuif F-94805, France;
authors.forename: Dana
authors.initials: D
authors.lastname: Hartl
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France;
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bidart
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1050 Brussels, Belgium; and.
authors.forename: Xavier
authors.initials: X
authors.lastname: De Deken
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 1050 Brussels, Belgium; and.
authors.forename: Françoise
authors.initials: F
authors.lastname: Miot
authors.affiliation: Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France; UMR 1018, INSERM, Villejuif F-94805, France.
authors.forename: Ibrahima
authors.initials: I
authors.lastname: Diallo
authors.affiliation: Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France; UMR 1018, INSERM, Villejuif F-94805, France.
authors.forename: Florent
authors.initials: F
authors.lastname: de Vathaire
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France;
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.affiliation: UMR 8200, CNRS, Villejuif F-94805, France; Institut Gustave Roussy, Villejuif F-94805, France; University Paris-Sud, Orsay F-91400, France; corinne.dupuy@gustaveroussy.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Dupuy
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D000074623:Dual Oxidases; D005110:Extracellular Space / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects*; D013961:Thyroid Gland / Q000201:enzymology / Q000473:pathology; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DNA damage; NADPH oxidase; ionizing radiation; oxidative stress; thyroid
references.citation: FEBS Lett. 2005 Aug 29;579(21):4911-7
references.pmid: 16111680
references.citation: Free Radic Biol Med. 2013 Dec;65:436-45
references.pmid: 23891676
references.citation: Nat Methods. 2006 Apr;3(4):281-6
references.pmid: 16554833
references.citation: J Biol Chem. 2006 Jul 7;281(27):18269-72
references.pmid: 16651268
references.citation: Physiol Rev. 2007 Jan;87(1):245-313
references.pmid: 17237347
references.citation: J Radiat Res. 2007 Mar;48(2):87-95
references.pmid: 17327686
references.citation: Free Radic Biol Med. 2007 Aug 1;43(3):332-47
references.pmid: 17602948
references.citation: Free Radic Biol Med. 2008 Sep 15;45(6):929-38
references.pmid: 18640264
references.citation: J Biol Chem. 1999 Dec 24;274(52):37265-9
references.pmid: 10601291
references.citation: J Biol Chem. 2000 Jul 28;275(30):23227-33
references.pmid: 10806195
references.citation: Radiat Res. 2000 Dec;154(6):659-66
references.pmid: 11096422
references.citation: Nature. 2003 Nov 13;426(6963):194-8
references.pmid: 14608368
references.citation: Nat Cell Biol. 2004 Feb;6(2):168-70
references.pmid: 14755273
references.citation: Mol Cell. 2004 May 21;14(4):501-13
references.pmid: 15149599
references.citation: Int J Radiat Biol. 2004 Apr;80(4):251-9
references.pmid: 15204702
references.citation: Nature. 1991 Jan 31;349(6308):431-4
references.pmid: 1992344
references.citation: Radiat Res. 1994 Apr;138(1 Suppl):S85-8
references.pmid: 8146335
references.citation: PLoS Biol. 2008 Dec 2;6(12):2853-68
references.pmid: 19053174
references.citation: J Biol Chem. 2009 Mar 13;284(11):6725-34
references.pmid: 19144650
references.citation: FASEB J. 2009 Apr;23(4):1205-18
references.pmid: 19074510
references.citation: Nat Cell Biol. 2009 Aug;11(8):973-9
references.pmid: 19597488
references.citation: Endocr Relat Cancer. 2009 Sep;16(3):845-56
references.pmid: 19509065
references.citation: Cancer Res. 2009 Oct 15;69(20):7917-25
references.pmid: 19826058
references.citation: Endocr Relat Cancer. 2010 Mar;17(1):27-37
references.pmid: 19779036
references.citation: Free Radic Biol Med. 2010 Jan 15;48(2):348-56
references.pmid: 19925862
references.citation: Mol Syst Biol. 2010;6:347
references.pmid: 20160708
references.citation: Cancer Res. 2010 May 15;70(10):4123-32
references.pmid: 20424115
references.citation: Endocr Rev. 2010 Oct;31(5):756-73
references.pmid: 20650861
references.citation: J Immunol. 2011 Apr 15;186(8):4762-70
references.pmid: 21411736
references.citation: EMBO J. 2011 Apr 20;30(8):1536-48
references.pmid: 21399611
references.citation: Cell. 2011 Apr 29;145(3):435-46
references.pmid: 21529715
references.citation: Oncol Rep. 2011 Aug;26(2):383-8
references.pmid: 21567101
references.citation: Cancer Lett. 2012 Dec 31;327(1-2):48-60
references.pmid: 22182453
references.citation: Free Radic Biol Med. 2013 Mar;56:216-25
references.pmid: 23010498
references.citation: Cell Rep. 2013 Apr 25;3(4):1252-65
references.pmid: 23562156
references.citation: J Gerontol A Biol Sci Med Sci. 2005 Nov;60(11):1386-93
references.pmid: 16339323