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Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach

Abstract : Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.
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https://hal.univ-reims.fr/hal-03377128
Contributor : Jean-Marc Ferez Connect in order to contact the contributor
Submitted on : Thursday, October 14, 2021 - 8:56:01 AM
Last modification on : Saturday, January 15, 2022 - 3:15:07 AM

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Jonathan Dauvé, Nicolas Belloy, Romain Rivet, Nicolas Etique, Pierre Nizet, et al.. Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach. Cancers, MDPI, 2021, 13 (19), pp.4930. ⟨10.3390/cancers13194930⟩. ⟨hal-03377128⟩

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