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PMID: 24583638 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation.

Cell death and differentiation ·Vol. 21 ·No. 6 ·2014-06-00 ·Pages 998-1012

Ogrunc M, Di Micco R, Liontos M, Bombardelli L, Mione M, Fumagalli M, Gorgoulis VG, d'Adda di Fagagna F

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.

MeSH Terms
Animals Cell Line, Tumor Cell Proliferation/drug effects DNA Damage/drug effects,genetics Humans Mice NADPH Oxidase 4 NADPH Oxidases/genetics,metabolism Oxidation-Reduction Oxidative Stress Pancreatic Neoplasms/genetics,pathology Reactive Oxygen Species/metabolism,toxicity Xenograft Model Antitumor Assays rac1 GTP-Binding Protein/genetics,metabolism
Chemicals
RAC1 protein, human Reactive Oxygen Species NADPH Oxidase 4 NADPH Oxidases NOX4 protein, human rac1 GTP-Binding Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Ogrunc M
IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
Di Micco R
IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
Liontos M
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece.
Bombardelli L ORCID
IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
Mione M
IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
Fumagalli M
IFOM Foundation, The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, Milan, Italy.
Gorgoulis V G
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.
d'Adda di Fagagna F
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.
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Article Info
Journal
Cell death and differentiation
Abbr.
Cell Death Differ
ISSN
1476-5403
DOI
10.1038/cdd.2014.16
Published
2014-06-00
Epub
2014-00-28
Pages
998-1012
Language
English
Region
England
NLM ID
9437445
PMCID
PMC4013514
Subset
IM
Grants
European Research Council · 322726 · International
Telethon · GGP12059 · Italy
External Links
PubMed source DOI: 10.1038/cdd.2014.16 PMC Full Text View journal details
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