Targeting the MMP-14/MMP-2/integrin v3 axis with multispecific N-TIMP2– based antagonists for cancer therapy

Gal Yosef, Valeria Arkadash, Niv Papo

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The pathophysiological functions of the signaling molecules matrix metalloproteinase-14 (MMP-14) and integrinv3 in various types of cancer are believed to derive from their collaborative activity in promoting invasion, metastasis, and angiogenesis, as shown in vitro and in vivo. The two effectors act in concert in a cell-specific manner through the localization of pro-MMP-2 to the cell surface, where it is processed to intermediate and matured MMP-2. The matured MMP-2 product is localized to the cell surface via its binding to integrinv3. The MMP-14/MMP-2/integrinv3 axis thus constitutes an attractive putative target for therapeutic interventions, but the development of inhibitors that target this axis remains an unfulfilled task. To address the lack of such multitarget inhibitors, we have established a combinatorial approach that is based on flow cytometry screening of a yeast-displayed N-TIMP2 (N-terminal domain variant of tissue inhibitor of metalloproteinase-2) mutant library. On the basis of this screening, we generated protein monomers and a heterodimer that contain monovalent and bivalent binding epitopes to MMP-14 and integrinv3. Among these proteins, the bi-specific heterodimer, which bound strongly to both MMP-14 and integrinv3, exhibited superior ability to inhibit MMP-2 activation and displayed the highest inhibitory activity in cell-based models of a MMP-14-, MMP-2-, and integrinv3-dependent glioblastoma and of endothelial cell invasiveness and endothelial capillary tube formation. These assays enabled us to show the superiority of the combined target effects of the inhibitors and to investigate separately the role each of the three signaling molecules in various malignant processes.

Original languageEnglish
Pages (from-to)13310-13326
Number of pages17
JournalJournal of Biological Chemistry
Volume293
Issue number34
DOIs
StatePublished - 24 Aug 2018

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