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Published on: June 2, 2022

Inhibition of matrix metalloproteinase 14 (MMP-14)-mediated cancer cell migration

Kevin Zarrabi1, Antoine Dufour, Jian Li

  • 1Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York 11794, USA.

The Journal of Biological Chemistry
|July 29, 2011
PubMed

Insights

Matrix metalloproteinase-14 (MMP-14) drives cancer metastasis via its hemopexin domain. Novel peptides targeting this domain inhibit metastasis without affecting tumor growth, offering a new therapeutic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Matrix metalloproteinases (MMPs) facilitate extracellular matrix remodeling and cell migration, crucial for cancer metastasis.
  • MMP-14, a membrane-anchored MMP, is particularly implicated in these metastatic processes.
  • The hemopexin (PEX) domain of MMP-14 is hypothesized to mediate cell migration through MMP-14 homodimerization and heterodimerization with CD44.

Purpose of the Study:

  • To identify the minimal functional regions within the MMP-14 PEX domain responsible for cell migration.
  • To investigate the role of specific PEX domain regions in MMP-14 homodimerization and CD44 heterodimerization.
  • To develop and evaluate peptide inhibitors targeting the MMP-14 PEX domain for anti-metastatic therapy.

Main Methods:

  • Site-directed mutagenesis to probe functional regions within the MMP-14 PEX domain.
  • Analysis of MMP-14 homodimerization and CD44 heterodimerization.
  • Design and synthesis of peptides mimicking critical PEX domain motifs.
  • In vitro assays to assess peptide inhibition of MMP-14-enhanced cell migration and metastasis models.

Main Results:

  • Mutagenesis identified Blades I and IV of the PEX domain as critical for cell migration.
  • Blade IV is essential for MMP-14 homodimerization, while Blade I is required for CD44-MMP-14 heterodimerization.
  • MMP-14/CD44 cross-talk activates EGF receptor, MAPK, and PI3K signaling pathways.
  • Synthetic peptides targeting the PEX domain effectively inhibited MMP-14-mediated cell migration and metastasis in a dose-dependent manner.
  • These peptides demonstrated efficacy against metastasis without impacting primary tumor growth.

Conclusions:

  • The MMP-14 PEX domain contains essential regions (Blades I and IV) critical for mediating cancer cell migration and metastasis.
  • Targeting the MMP-14 PEX domain with specific peptide inhibitors represents a promising and selective strategy to combat cancer dissemination.
  • This approach offers a novel therapeutic avenue for inhibiting metastasis without compromising primary tumor development.

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