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

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.

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…Semaphorins can also undertake “reverse signalling” in which rather than acting as ligands they act as receptors and initiate a signalling response through their own cytoplasmic domains [ 129 , 130 ]. Thus, the semaphorins have multifaceted properties in neurodevelopment and in the pathological CNS following injury or disease [ 131 , 132 , 133 , 134 , 135 , 136 , 137 ].…”

Bone Marrow Endothelial Cells Increase Prostate Cancer Cell Apoptosis in 3D Triculture Model of Reactive Stroma

“…Activation of PCa growth can occur downstream of various cell-surface signaling events through receptors such as plexin-semaphorins, TGFβRIII, and c-Met [ 8 , 9 , 18 ]. FOXM1, a transcription factor, is known as a master regulator in growing cancers, where it plays an essential role in sustaining proliferation [ 39 ].…”

“…For triculture and conditioned media experiments, PCa cells were pre-clustered using microwell plates (Sphericalplate 5D, Kugelmeiers, Erlenbach, Switzerland) by dispensing 90,000 cells per well of a 24-well plate, as described previously [ 18 ]. Cells were allowed to cluster for 24 h before collecting and encapsulating them.…”

Gabapentin Disrupts Binding of Perlecan to the α2δ1Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation

“…Full-length PLN was isolated and purified from HT-29 human colorectal cancer cells (formerly called WiDr) (ATCC, Manassas, VA, USA) as reported 63, 64 ( Suppl. Methods ).…”