Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis

Plasminogen activator inhibitor 1 (PAI-1) has been found to be a bad progno stic factor in a number of tumours but the reason has not been fully explai ned. The human prostate cancer cell line PC-3 and the human promyelocytic l eukaemia cell line HL-60 were used in this study to determine the effect of PAI-1 on spontaneous and induced apoptosis in culture. Apoptosis was induc ed with camptothecin or etoposide. Addition of a stable variant of PAI-1 or wild-type PAI-1 to these cells resulted in a significant inhibition of apo ptosis. In contrast, both the latent form of PAI-1 and the stable variant o f PAI-1 inactivated by a specific neutralizing monoclonal antibody, or the stable variant of PAI-1 in a complex with recombinant urokinase did not inh ibit apoptosis. This indicated that the inhibitory activity of PAI-1 was re quired for its anti-apoptotic effect but the urokinase-type plasminogen act ivator receptor was not involved. These findings provide an explanation for the bad prognostic correlation of high PAI-1 levels in tumours. The anti-a poptotic effect was also found in non-tumoural cells including human umbili cal vein endothelial cells and the benign human breast epithelial cell line MCF-10A, suggesting that this is a novel physiologic function of PAI-1. (C ) 2000 Cancer Research Campaign.