Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2018

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

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1
Eléonore Lambert
  • Function : Author
Eloïse Fuselier
  • Function : Author
Laurent Ramont
Bertrand Brassart
  • Function : Author
Jean-Baptiste Oudart
  • Function : Author
Aurélie Dupont-Deshorgue
Christèle Sellier
Carine Machado
  • Function : Author
Manuel Dauchez
Jean-Claude Monboisse
  • Function : Author
François-Xavier Maquart
  • Function : Author
Stéphanie Baud
Sylvie Brassart-Pasco

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.

Dates and versions

hal-02310422 , version 1 (10-10-2019)

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Eléonore Lambert, Eloïse Fuselier, Laurent Ramont, Bertrand Brassart, Sylvain Dukic, et al.. Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition. Scientific Reports, 2018, 8 (1), ⟨10.1038/s41598-018-28003-x⟩. ⟨hal-02310422⟩
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