Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis.
The coagulation and fibrinolytic systems contribute to malignancy by increasing angiogenesis, tumor growth, tumor invasion, and tumor metastasis. Oncogenic transformation increases the expression of tissue factor (TF) that results in local generation of coagulation proteases and activation of protease-activated receptor (PAR)-1 and PAR-2. We compared the PAR-dependent expression of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 in 2 murine mammary adencocarcinoma cell lines: metastatic 4T1 cells and nonmetastatic 67NR cells. 4T1 cells expressed TF, PAR-1 and PAR-2 whereas 67NR cells expressed TF and PAR-1. We also silenced PAR-1 or PAR-2 expression in the 4T1 cells. We discovered 2 distinct mechanisms for PAR-dependent expression of uPA and PAI-1. First, we found that factor Xa or thrombin activation of PAR-1 led to a rapid release of stored intracellular uPA into the culture supernatant. Second, thrombin transactivation of a PAR-1/PAR-2 complex resulted in increases in PAI-1 mRNA and protein expression. Cells lacking PAR-2 failed to express PAI-1 in response to thrombin and factor Xa did not activate the PAR-1/PAR-2 complex. Our results reveal how PAR-1 and PAR-2 on tumor cells mediate crosstalk between coagulation and fibrinolysis.
McEachron
Troy A
TA
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Pawlinski
Rafal
R
Richards
Kristy L
KL
Church
Frank C
FC
Mackman
Nigel
N
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005342:Fibrinolysis / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015151:Immunoblotting; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D044462:Receptors, Proteinase-Activated; D014568:Urokinase-Type Plasminogen Activator