Conformation-dependent binding of a Tetrastatin peptide to α v β 3 integrin decreases melanoma progression through FAK/PI 3 K/Akt pathway inhibition

• Published in: Scientific reports Vol. 8; no. 1; p. 9837
• Main Authors: Lambert, Eléonore, Fuselier, Eloïse, Ramont, Laurent, Brassart, Bertrand, Dukic, Sylvain, Oudart, Jean-Baptiste, Dupont-Deshorgue, Aurélie, Sellier, Christèle, Machado, Carine, Dauchez, Manuel, Monboisse, Jean-Claude, Maquart, François-Xavier, Baud, Stéphanie, Brassart-Pasco, Sylvie
• Format: Journal Article
• Language: English
• Published: England 29.06.2018
• ISSN: 2045-2322

Tetrastatin, a 230 amino acid sequence from collagen IV, was previously demonstrated to inhibit melanoma progression. In the present paper, we identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin in vivo and in vitro on melanoma cell proliferation, migration and invasion. We demonstrated that QS-13 binds to SK-MEL-28 melanoma cells through the α β integrin using blocking antibody and β3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with α β integrin were analyzed by docking experiments to determine the binding areas and the QS-13 amino acids crucial for the binding. The in silico results were confirmed by in vitro experiments. Indeed, QS-13 binding to SK-MEL-28 was dependent on the presence of a disulfide-bound as shown by mass spectroscopy and the binding site on α β was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PI K/Akt pathway, a transduction pathway that is largely involved in tumor cell proliferation and migration. Taken together, our results demonstrate that the QS-13 peptide binds α β integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through α β .