Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition

Abstract 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 me...

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Autores principales:	Eléonore Lambert, Eloïse Fuselier, Laurent Ramont, Bertrand Brassart, Sylvain Dukic, Jean-Baptiste Oudart, Aurélie Dupont-Deshorgue, Christèle Sellier, Carine Machado, Manuel Dauchez, Jean-Claude Monboisse, François-Xavier Maquart, Stéphanie Baud, Sylvie Brassart-Pasco
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b13252cfd5e842f7aba5081827f0d566
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spelling	oai:doaj.org-article:b13252cfd5e842f7aba5081827f0d5662021-12-02T15:09:12ZConformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition10.1038/s41598-018-28003-x2045-2322https://doaj.org/article/b13252cfd5e842f7aba5081827f0d5662018-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-28003-xhttps://doaj.org/toc/2045-2322Abstract 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 αvβ3 integrin using blocking antibody and β3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αVβ3 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 αVβ3 was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PI3K/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 αvβ3 integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αVβ3.Eléonore LambertEloïse FuselierLaurent RamontBertrand BrassartSylvain DukicJean-Baptiste OudartAurélie Dupont-DeshorgueChristèle SellierCarine MachadoManuel DauchezJean-Claude MonboisseFrançois-Xavier MaquartStéphanie BaudSylvie Brassart-PascoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eléonore Lambert Eloïse Fuselier Laurent Ramont Bertrand Brassart Sylvain Dukic Jean-Baptiste Oudart Aurélie Dupont-Deshorgue Christèle Sellier Carine Machado Manuel Dauchez Jean-Claude Monboisse François-Xavier Maquart Stéphanie Baud Sylvie Brassart-Pasco Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
description	Abstract 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 αvβ3 integrin using blocking antibody and β3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αVβ3 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 αVβ3 was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PI3K/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 αvβ3 integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αVβ3.
format	article
author	Eléonore Lambert Eloïse Fuselier Laurent Ramont Bertrand Brassart Sylvain Dukic Jean-Baptiste Oudart Aurélie Dupont-Deshorgue Christèle Sellier Carine Machado Manuel Dauchez Jean-Claude Monboisse François-Xavier Maquart Stéphanie Baud Sylvie Brassart-Pasco
author_facet	Eléonore Lambert Eloïse Fuselier Laurent Ramont Bertrand Brassart Sylvain Dukic Jean-Baptiste Oudart Aurélie Dupont-Deshorgue Christèle Sellier Carine Machado Manuel Dauchez Jean-Claude Monboisse François-Xavier Maquart Stéphanie Baud Sylvie Brassart-Pasco
author_sort	Eléonore Lambert
title	Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
title_short	Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
title_full	Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
title_fullStr	Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
title_full_unstemmed	Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition
title_sort	conformation-dependent binding of a tetrastatin peptide to αvβ3 integrin decreases melanoma progression through fak/pi3k/akt pathway inhibition
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/b13252cfd5e842f7aba5081827f0d566
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Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition

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