Regulation of NADPH-dependent Nitric Oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH analogue
Metrics: PDF 2520 views | HTML 2804 views | ?
Florian Rouaud1, Miguel Romero-Perez2, Huan Wang3, Irina Lobysheva2, Booma Ramassamy4, Etienne Henry3, Patrick Tauc3, Damien Giacchero5, Jean-Luc Boucher4, Eric Deprez3, Stéphane Rocchi1 and Anny Slama-Schwok6
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
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
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 NOX4 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 NOX4 –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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.