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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 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.
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https://hal.univ-reims.fr/hal-02310422
Contributor : Brigitte Perron Connect in order to contact the contributor
Submitted on : Thursday, October 10, 2019 - 10:42:29 AM
Last modification on : Tuesday, March 1, 2022 - 7:33:51 AM

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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, Nature Publishing Group, 2018, 8 (1), ⟨10.1038/s41598-018-28003-x⟩. ⟨hal-02310422⟩

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