Activation of EGFR by small compounds through coupling the generation of hydrogen peroxide to stable dimerization of Cu/Zn SOD1

Vehary Sakanyan (1, 2) , Philippe Hulin (3) , Rodolphe Alves de Sousa (4) , Viviane Silva (5) , Artur Hambardzumyan (6) , Steven Nedellec (3) , Christophe Tomasoni (2) , Cédric Logé (2) , Charles Pineau (7, 8) , Christos Roussakis (2) , Fabrice Fleury (5) , Isabelle Artaud (4)

1 ProtNeteomix
2 IICiMed - Cibles et Médicaments des Infections et de l'Immunité
3 Plateforme MicroPicell [Nantes]
4 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
5 UFIP - Unité de fonctionnalité et ingénierie de protéines
6 SPC Armbiotechnology
7 Irset - Institut de recherche en santé, environnement et travail
8 Protim - Proteomics Core Facility

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.

Domaines: Chimie; Sciences du Vivant [q-bio]

Vehary Sakanyan, Philippe Hulin, Rodolphe Alves de Sousa, Viviane Silva, Artur Hambardzumyan, et al.. Activation of EGFR by small compounds through coupling the generation of hydrogen peroxide to stable dimerization of Cu/Zn SOD1. Scientific Reports, 2016, 6 (1), pp.21088. ⟨10.1038/srep21088⟩. ⟨hal-03652537⟩