Background:
Enhanced expression and activation of metalloproteinase-9 (MMP9) is associated with mantle cell
lymphoma (MCL) progression, invasion and metastasis.
Objective:
To find potential peptide inhibitor against MMP9, which in turn, could inhibit MCL progression.
Methods:
We performed CCK8 assay, western blot and transwell assays for RNAi activity. Molecular Operating
Environment (MOE) software was applied for structural optimization as MMP9 and peptides were docked. We used gelatin
zymography and confocal microscopy confirm that the peptides can inhibit MMP9 activity. We applied CCK8 and transwell
assay to evaluate cell proliferation and metastasis and flow cytometry to evaluate cell cycle progression and apoptosis.
Results:
High MMP9 expression was observed in 49 of 88 samples (55.7%). Patients with high MMP9 expression were
more likely to present with high stage (Stage 3-4, P=0.01), bone marrow invasion (P=0.033) and high level LDH (P=0.000).
High MMP9 expression was associated with significantly shorter overall survival (OS, HR=2.378, P=0.012) and
progression free survival (PFS, HR=2.068, P=0.03). Multivariate analysis identified high MMP9 expression (P= 0.027),
high-risk mantle cell lymphoma international prognostic index (MIPI, HR=2.327, P=0.023), and no radiation therapy
(P=0.035) as adverse prognostic factors. Silencing of MMP9 in Jeko-1 cells by RNAi suppressed cells migration and
invasion in vitro (P<0.05). According to the docking results, peptide M3 bound deeply in the binding pocket of MMP9 and
had interaction with the active-site Zn2+ ion in the catalytic domain. M3 was not only compatible with MMP9, but also
inhibited its activity. M3 inhibited Jeko-1 cells proliferation, metastasis and cell cycle progression, and promoted cell
apoptosis rate (P<0.05).
Conclusion:
We designed M3 through structure-based molecular docking, which can specifically bind to MMP9 and inhibit
the activity of MMP9. M3 could be a potential antagonist as the treatment of MCL with MMP9 overexpression.
Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma