title: Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation.
abstract: Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents.
authors.affiliation: IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ogrunc
authors.affiliation: IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Di Micco
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Liontos
authors.affiliation: IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
authors.forename: L
authors.identifier: 0000000302132747
authors.initials: L
authors.lastname: Bombardelli
authors.affiliation: IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mione
authors.affiliation: IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fumagalli
authors.affiliation: 1] Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece [2] Basic Science II Center, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 11527 Athens, Greece.
authors.forename: V G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: 1] IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy [2] Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, via Abbiategrasso 207, Pavia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D020830:rac1 GTP-Binding Protein