Molecular competition between plasminogen activator inhibitors type -1 and -2 for urokinase: implications for cellular proteolysis and adhesion in cancer

Up-regulation of the urokinase plasminogen activation (uPA) system leads to increased

cancer invasion and metastasis. Plasminogen activator inhibitors type-1 (PAI-1/SERPINE1)

and type-2 (PAI-2/SERPINB2) have similar uPA inhibitory properties yet PAI-1 promotes

cell invasion by modulating cell adhesion and migration. High tumour PAI-2 levels are

associated with improved prognoses. Herein we show that PAI-2 is capable of inhibiting

uPA in the presence of PAI-1, particularly on adherent cells in the presence of vitronectin.

This suggests that elevated levels of PAI-2 in the tumour microenvironment could outcompete

PAI-1 for uPA inhibition through its inhibitory serpin function. However, PAI-1 modulated

cell adhesion in a largely uPA-independent manner consequently PAI-2 could not

counteract the effects of PAI-1 on adhesion/migration. Thus studies aimed at further characterising

the interplay between PAI-1 and PAI-2 on uPA-dependent pro-invasive processes

are warranted.