Identification of TAX2 peptide as a new unpredicted anti-cancer agent
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Albin Jeanne1,2,3, Emilie Sick1,4, Jérôme Devy1,2, Nicolas Floquet5, Nicolas Belloy2,6, Louis Theret1,2, Camille Boulagnon-Rombi2,7, Marie-Danièle Diebold2,7, Manuel Dauchez2,6, Laurent Martiny1,2, Christophe Schneider1,2, Stéphane Dedieu1,2
1Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France
2CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France
3SATT Nord, Lille, France
4Université de Strasbourg, CNRS UMR 7213, Illkirch, France
5Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR 5247, Université de Montpellier, Ecole Normale Supérieure de Chimie de Montpellier, Faculté de Pharmacie, Montpellier, France
6Plateforme de Modélisation Moléculaire Multi-échelle (P3M), Université de Reims Champagne-Ardenne, Reims, France
7CHU de Reims, Laboratoire Central d’Anatomie et de Cytologie Pathologiques, Reims, France
Stéphane Dedieu, e-mail: [email protected]
Keywords: TSP-1, CD47, CD36, cancer, angiogenesis
Received: March 24, 2015 Accepted: May 09, 2015 Published: May 22, 2015
The multi-modular glycoprotein thrombospondin-1 (TSP-1) is considered as a key actor within the tumor microenvironment. Besides, TSP-1 binding to CD47 is widely reported to regulate cardiovascular function as it promotes vasoconstriction and angiogenesis limitation. Therefore, many studies focused on targeting TSP-1:CD47 interaction, aiming for up-regulation of physiological angiogenesis to enhance post-ischemia recovery or to facilitate engraftment. Thus, we sought to identify an innovative selective antagonist for TSP-1:CD47 interaction. Protein-protein docking and molecular dynamics simulations were conducted to design a novel CD47-derived peptide, called TAX2. TAX2 binds TSP-1 to prevent TSP-1:CD47 interaction, as revealed by ELISA and co-immunoprecipitation experiments. Unexpectedly, TAX2 inhibits in vitro and ex vivo angiogenesis features in a TSP-1-dependent manner. Consistently, our data highlighted that TAX2 promotes TSP-1 binding to CD36-containing complexes, leading to disruption of VEGFR2 activation and downstream NO signaling. Such unpredicted results prompted us to investigate TAX2 potential in tumor pathology. A multimodal imaging approach was conducted combining histopathological staining, MVD, MRI analysis and μCT monitoring for tumor angiography longitudinal follow-up and 3D quantification. TAX2 in vivo administrations highly disturb syngeneic melanoma tumor vascularization inducing extensive tumor necrosis and strongly inhibit growth rate and vascularization of human pancreatic carcinoma xenografts in nude mice.
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