Cleavage of the Perlecan-Semaphorin 3A-Plexin A1-Neuropilin-1 (PSPN) Complex by Matrix Metalloproteinase 7/Matrilysin Triggers Prostate Cancer Cell Dyscohesion and Migration.

Tristen V Tellman,Mary C Farach-Carson,Lissette A Cruz,Brian J Grindel

doi:10.3390/ijms22063218

Abstract

The Perlecan-Semaphorin 3A-Plexin A1-Neuropilin-1 (PSPN) Complex at the cell surface of prostate cancer (PCa) cells influences cell–cell cohesion and dyscohesion. We investigated matrix metalloproteinase-7/matrilysin (MMP-7)’s ability to digest components of the PSPN Complex in bone metastatic PCa cells using in silico analyses and in vitro experiments. Results demonstrated that in addition to the heparan sulfate proteoglycan, perlecan, all components of the PSPN Complex were degraded by MMP-7. To investigate the functional consequences of PSPN Complex cleavage, we developed a preformed microtumor model to examine initiation of cell dispersion after MMP-7 digestion. We found that while perlecan fully decorated with glycosaminoglycan limited dispersion of PCa microtumors, MMP-7 initiated rapid dyscohesion and migration even with perlecan present. Additionally, we found that a bioactive peptide (PLN4) found in perlecan domain IV in a region subject to digestion by MMP-7 further enhanced cell dispersion along with MMP-7. We found that digestion of the PSPN Complex with MMP-7 destabilized cell–cell junctions in microtumors evidenced by loss of co-registration of E-cadherin and F-actin. We conclude that MMP-7 plays a key functional role in PCa cell transition from a cohesive, indolent phenotype to a dyscohesive, migratory phenotype favoring production of circulating tumor cells and metastasis to bone.

Highlights

Among the non-collagenous components of the extracellular matrix, the large heparan sulfate proteoglycan perlecan/heparan sulfate proteoglycan 2 (HSPG2) plays a unique role in coordination of signaling complexes on the surfaces of the cells that it engages
Using a preformed microtumor model developed for this project, we examined the initiation of cell migration after matrix metalloproteinase-7/matrilysin (MMP-7) digestion and tested the hypothesis that the bioactive perlecan 4 (PLN4) peptide produced by matrix metalloproteinase (MMP)-7 digestion of perlecan could further enhance cell migration
Subsequent in vitro digestions demonstrated that MMP-7 proteolysis can destroy all components of the Perlecan-Semaphorin 3A-Plexin A1-Neuropilin-1 (PSPN) Complex, an event that we showed favors dyscohesion, dispersion and cell migration, events associated with formation of circulating tumor cells (CTCs) and metastasis in

Summary

Introduction

Among the non-collagenous components of the extracellular matrix, the large heparan sulfate proteoglycan perlecan/heparan sulfate proteoglycan 2 (HSPG2) plays a unique role in coordination of signaling complexes on the surfaces of the cells that it engages. As we previously proposed [1], perlecan can be considered as an extracellular scaffolding protein in which each of its five structural domains interacts with various classes of surface complexes including growth factor receptors (domain I), low-density lipoproteins Perlecan domain IV-3 (Dm IV-3), the last seven Ig repeats, interacts with semaphorin 3A (Sema3A) in complex with cell-surface plexin A1 and neuropilin-1 (NRP1) to regulate epithelial cell adhesion and dyscohesion [4]. Control of this clustering behavior by Dm. IV-3 has been observed in both cancer [5] and normal [6,7] cells. Plexins and semaphorins influence cell migration through integrin activation and cytoskeletal reorganization [8]

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Conclusion