Research Papers:

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

Florian Rouaud, Miguel Romero-Perez, Huan Wang, Irina Lobysheva, Booma Ramassamy, Etienne Henry, Patrick Tauc, Damien Giacchero, Jean-Luc Boucher, Eric Deprez, Stéphane Rocchi and Anny Slama-Schwok _

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Oncotarget. 2014; 5:10650-10664. https://doi.org/10.18632/oncotarget.2525

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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.

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