title: Activation of EGFR by small compounds through coupling the generation of hydrogen peroxide to stable dimerization of Cu/Zn SOD1.
abstract: Activation of cell signaling by reactive chemicals and pollutants is an important issue for human health. It has been shown that lipophilic nitro-benzoxadiazole (NBD) compounds rapidly move across the plasma membrane and enhance Epidermal Growth Factor Receptor (EGFR) tyrosine phosphorylation in cancer cells. Unlike ligand-dependent activation, the mechanism of this induction relies on the generation of hydrogen peroxide, which is involved in the activation of the catalytic site of the receptor and the inactivation of protein tyrosine phosphatase PTP-1B. Production of H2O2 during redox transformation of NBD compounds is associated with the transition of a monomeric form of Cu/Zn superoxide dismutase 1 (SOD1) to stable dimers. The highly stable and functionally active SOD1 dimer, in the absence of adequate activities in downstream reactions, promotes the disproportionate production and accumulation of intracellular hydrogen peroxide shortly after exposure to NBD compounds. The intrinsic fluorescence of small compounds was used to demonstrate their binding to SOD1. Our data indicate that H2O2 and concomitantly generated electrophilic intermediates behave as independent entities, but all contribute to the biological reactivity of NBD compounds. This study opens a promising path to identify new biomarkers of oxidative/electrophilic stress in the progression of cancer and other diseases.
authors.affiliation: IICiMed EA-1155, Faculté de Pharmacie, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.|ProtNeteomix, 29 rue de Provence, 44700 Orvault, France.
authors.forename: Vehary
authors.initials: V
authors.lastname: Sakanyan
authors.affiliation: Plate-forme MicroPICell SFR Santé F. Bonamy-FED 4203/Inserm UMS016/CNRS UMS3556, 44007 Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hulin
authors.affiliation: UMR 8601, CNRS, Université Paris Descartes, PRES Paris cité, 45 rue des Saints-Pères, 75270 Paris Cedex06, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Alves de Sousa
authors.affiliation: UFIP CNRS UMR 6286, Mechanism and Regulation of DNA Repair team, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Viviane A O
authors.initials: VA
authors.lastname: Silva
authors.affiliation: SPC Armbiotechnology, 14, Gyurjyan str.,Yerevan 0056, Armenia.
authors.forename: Artur
authors.initials: A
authors.lastname: Hambardzumyan
authors.affiliation: Plate-forme MicroPICell SFR Santé F. Bonamy-FED 4203/Inserm UMS016/CNRS UMS3556, 44007 Nantes, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.affiliation: IICiMed EA-1155, Faculté de Pharmacie, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tomasoni
authors.affiliation: IICiMed EA-1155, Faculté de Pharmacie, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.affiliation: Protim, Inserm U1085-Irset, Campus de Beaulieu, 35042 Rennes, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Pineau
authors.affiliation: IICiMed EA-1155, Faculté de Pharmacie, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Roussakis
authors.affiliation: UFIP CNRS UMR 6286, Mechanism and Regulation of DNA Repair team, Faculté des Sciences et des Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Fleury
authors.affiliation: UMR 8601, CNRS, Université Paris Descartes, PRES Paris cité, 45 rue des Saints-Pères, 75270 Paris Cedex06, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Artaud