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

SIMPLE SUMMARY: This work aimed to investigate the interactions of lumican-derived peptides and MMP-14. An in silico approach unraveled key residues in the amino acid sequence of MMP-14 interacting with the Small Leucine-Rich Proteoglycan (SLRP) lumican-derived peptides. The in silico docking analysis demonstrated that the interaction of a cyclic lumican-derived peptide (L9Mc, 12 amino acids) with MMP-14 was preferential with the MT-Loop domain of MMP-14 while the linear lumican-derived peptide (lumcorin, 17 amino acids) interacted more with the catalytic site. L9Mc significantly inhibited the migration of murine B16F1 but not human HT-144 melanoma cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. This result led us to investigate the effect of L9Mc on cell proliferation, which is independent of MMP-14 activity. L9Mc significantly inhibited the proliferation of B16F1 but not HT-144 melanoma cells in vitro and primary melanoma tumor growth. Altogether, the biological assays validated the prediction of the in silico study. 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.