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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doaj-b13252cfd5e842f7aba5081827f0d5662020-12-08T06:22:56ZengNature Publishing GroupScientific Reports2045-23222018-06-018111310.1038/s41598-018-28003-xConformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibitionEléonore Lambert0Eloïse Fuselier1Laurent Ramont2Bertrand Brassart3Sylvain Dukic4Jean-Baptiste Oudart5Aurélie Dupont-Deshorgue6Christèle Sellier7Carine Machado8Manuel Dauchez9Jean-Claude Monboisse10François-Xavier Maquart11Stéphanie Baud12Sylvie Brassart-Pasco13UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)CNRS UMR 7312, Institut de Chimie Moléculaire de Reims, Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA)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.https://doi.org/10.1038/s41598-018-28003-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2018-06-01 |
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. |
url |
https://doi.org/10.1038/s41598-018-28003-x |
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