Activated thrombin-activatable fibrinolysis inhibitor TAFIa attenuates breast cancer cell metastatic behaviors through inhibition of plasminogen activation and extracellular proteolysisReport as inadecuate




Activated thrombin-activatable fibrinolysis inhibitor TAFIa attenuates breast cancer cell metastatic behaviors through inhibition of plasminogen activation and extracellular proteolysis - Download this document for free, or read online. Document in PDF available to download.

BMC Cancer

, 16:328

Cell and molecular biology

Abstract

BackgroundThrombin activatable fibrinolysis inhibitor TAFI is a plasma zymogen, which can be converted to activated TAFI TAFIa through proteolytic cleavage by thrombin, plasmin, and most effectively thrombin in complex with the endothelial cofactor thrombomodulin TM. TAFIa is a carboxypeptidase that cleaves carboxyl terminal lysine and arginine residues from protein and peptide substrates, including plasminogen-binding sites on cell surface receptors. Carboxyl terminal lysine residues play a pivotal role in enhancing cell surface plasminogen activation to plasmin. Plasmin has many critical functions including cleaving components of the extracellular matrix ECM, which enhances invasion and migration of cancer cells. We therefore hypothesized that TAFIa could act to attenuate metastasis.

MethodsTo assess the role of TAFIa in breast cancer metastasis, in vitro migration and invasion assays, live cell proteolysis and cell proliferation using MDA-MB-231 and SUM149 cells were carried out in the presence of a TAFIa inhibitor, recombinant TAFI variants, or soluble TM.

ResultsInhibition of TAFIa with potato tuber carboxypeptidase inhibitor increased cell invasion, migration and proteolysis of both cell lines, whereas addition of TM resulted in a decrease in all these parameters. A stable variant of TAFIa, TAFIa-CIIYQ, showed enhanced inhibitory effects on cell invasion, migration and proteolysis. Furthermore, pericellular plasminogen activation was significantly decreased on the surface of MDA-MB-231 and SUM149 cells following treatment with various concentrations of TAFIa.

ConclusionsTaken together, these results indicate a vital role for TAFIa in regulating pericellular plasminogen activation and ultimately ECM proteolysis in the breast cancer microenvironment. Enhancement of TAFI activation in this microenvironment may be a therapeutic strategy to inhibit invasion and prevent metastasis of breast cancer cells.

KeywordsTAFI Thrombomodulin Breast cancer Metastasis Extracellular proteolysis Plasminogen AbbreviationsECMextracellular matrix

FDPsfibrin degradation products

MMPmatrix metalloproteinase

PASplasminogen activation system

PTCIpotato tuber carboxypeptidase inhibitor

TAFIthrombin activatable fibrinolysis inhibitor

TAFIaactivated thrombin activatable fibrinolysis inhibitor

TMthrombomodulin

tPAtissue-type plasminogen activator

uPAurokinase plasminogen activator

uPARurokinase plasminogen activator receptor

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Author: Zainab A. Bazzi - Danielle Lanoue - Mouhanned El-Youssef - Rocco Romagnuolo - Janice Tubman - Dora Cavallo-Medved - Lisa A

Source: https://link.springer.com/







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