Regulation of NADPH-dependent Nitric Oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH analogue

This is the authors' abstract. We don't add key points for this paper.

// Florian Rouaud 1 , Miguel Romero-Perez 2 , Huan Wang 3 , Irina Lobysheva 2 , Booma Ramassamy 4 , Etienne Henry 3 , Patrick Tauc 3 , Damien Giacchero 5 , Jean-Luc Boucher 4 , Eric Deprez 3 , Stéphane Rocchi 1 and Anny Slama-Schwok 6 1 INSERM U1065 team 1, Université de Nice Sophia Antipolis et Centre Méditerranéen de Médecine Moléculaire, Nice, France 2 Pole of Pharmacology and Therapeutics, FATH5349, IREC, UCL Medical Sector, Brussels, Belgium 3 Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), ENS-Cachan, CNRS UMR 8113, IDA FR3242, Cachan, France 4 CNRS UMR 8601, Université Paris Descartes, 45 rue des Saints Pères, Paris, France 5 Service de Dermatologie, Hôpital Archet II, CHU Nice, France; 6 Virologie et Immunologie Moléculaires, UR 892, INRA, Jouy en Josas, France Correspondence: Anny Slama-Schwok, email: // Stéphane Rocchi, email: // Keywords : Cellular signaling; Angiogenesis; NADPH analogue; cell proliferation; ROS; melanoma, endothelium Received : August 04, 2014 Accepted : September 24, 2014 Published : September 25, 2014 Abstract Nitric Oxide (NO) and Reactive oxygen species (ROS) are endogenous regulators of angiogenesis-related events as endothelial cell proliferation and survival, but NO/ROS defect or unbalance contribute to cancers. We recently designed a novel photoactive inhibitor of NO-Synthases (NOS) called NS1, which binds their NADPH site in vitro . Here, we show that NS1 inhibited NO formed in aortic rings. NS1-induced NO decrease led to an inhibition of angiogenesis in a model of VEGF-induced endothelial tubes formation. Beside this effect, NS1 reduced ROS levels in endothelial and melanoma A375 cells and in aorta. In metastatic melanoma cells, NS1 first induced a strong decrease of VEGF and blocked melanoma cell cycle at G2/M. NS1 decreased NOX 4 and ROS levels that could lead to a specific proliferation arrest and cell death. In contrast, NS1 did not perturb melanocytes growth. Altogether, NS1 revealed a possible cross-talk between eNOS- and NOX 4 –associated pathways in melanoma cells via VEGF, Erk and Akt modulation by NS1 that could be targeted to stop proliferation. NS1 thus constitutes a promising tool that modulates NO and redox stresses by targeting and directly inhibiting eNOS and, at least indirectly, NADPH oxidase(s), with great potential to control angiogenesis.